The Open Biotechnology Journal




ISSN: 1874-0707 ― Volume 13, 2019
REVIEW ARTICLE

Microbial Diversity of Mer Operon Genes and Their Potential Rules in Mercury Bioremediation and Resistance



Martha M. Naguib1, Ahmed O. El-Gendy2, Ahmed S. Khairalla2, *
1 Department of Biotechnology and Life Sciences, Faculty of Post Graduate Studies for Advanced Sciences, Beni-Suef University, Beni-Suef 62511, Egypt
2 Department of Microbiology and Immunology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62511, Egypt

Abstract

Background:

Mercury is a toxic metal that is present in small amounts in the environment, but its level is rising steadily, due to different human activities, such as industrialization. It can reach humans through the food chain, amalgam fillings, and other sources, causing different neurological disorders, memory loss, vision impairment, and may even lead to death; making its detoxification an urgent task.

Methods:

Various physical and chemical mercury remediation techniques are available, which generally aim at: (i) reducing its mobility or solubility; (ii) causing its vaporization or condensation; (iii) its separation from contaminated soils. Biological remediation techniques, commonly known as bioremediation, are also another possible alternative, which is considered as cheaper than the conventional means and can be accomplished using either (i) organisms harboring the mer operon genes (merB, merA, merR, merP, merT, merD, merF, merC, merE, merH and merG), or (ii) plants expressing metal-binding proteins. Recently, different mer determinants have been genetically engineered into several organisms, including bacteria and plants, to aid in detoxification of both ionic and organic forms of mercury.

Results:

Bacteria that are resistant to mercury compounds have at least a mercuric reductase enzyme (MerA) that reduces Hg+2 to volatile Hg0, a membrane-bound protein (MerT) for Hg+2 uptake and an additional enzyme, MerB, that degrades organomercurials by protonolysis. Presence of both merA and merB genes confer broad-spectrum mercury resistance. However, merA alone confers narrow spectrum inorganic mercury resistance.

Conclusion:

To conclude, this review discusses the importance of mercury-resistance genes in mercury bioremediation. Functional analysis of mer operon genes and the recent advances in genetic engineering techniques could provide the most environmental friendly, safe, effective and fantastic solution to overcome mercuric toxicity.

Keywords: Mercury, Mercury toxicity, Biogeochemical cycle, Mercury remediation, Resistance mechanisms, Mer operon.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
First Page: 56
Last Page: 77
Publisher Id: TOBIOTJ-12-56
DOI: 10.2174/1874070701812010056

Article History:

Received Date: 27/10/2017
Revision Received Date: 23/2/2018
Acceptance Date: 16/03/2018
Electronic publication date: 30/04/2018
Collection year: 2018

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© 2018 Naguib et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department of Microbiology and immunology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62511, Egypt, Tel: +2-012-234-76015; E-mails: ahmed.elgendy@pharm.bsu.edu.eg, ahmedkhairalla@pharm.bsu.edu.eg




1. INTRODUCTION

For a long time, the term “heavy metals” had been widely used for metals associated with contamination and eco-toxicity. The International Union of Pure and Applied Chemistry (IUPAC) recommended using the term “toxic metal” as an alternative to “heavy metal” [1Report IT. Heavy Metals ”— A meaningless term ? (IUPAC Technical Report). 2002; 74(5): 793-807.]. Toxic metals are stable and persistent environmental contaminants [2Montuelle B, Latour X, Volat B, Gounot AM. Toxicity of heavy metals to bacteria in sediments. Bull Environ Contam Toxicol 1994; 53(5): 753-8.[http://dx.doi.org/10.1007/BF00196950] [PMID: 7833613] ]. Many metals such as mercury, cadmium, chromium, zinc, lead, copper, arsenic etc., used in different industries, are releasing its toxic ions and introducing it into the ecosystem leading to toxic effects, affecting humans, animals, plants, and microbial communities [3Nisa M, Coral Ü, Korkmaz H, Arikan B, Coral G. Plasmid mediated heavy metal resistances in Enterobacter spp. isolated from Sofulu landfill 2005; 55(3): 175-9.]. Also, some toxic metals naturally exist in very low concentrations in the ecosystem and are required in trace amounts as nutrients by microbial communities but in relatively higher concentration, they form toxic complexes on the biological cell [3Nisa M, Coral Ü, Korkmaz H, Arikan B, Coral G. Plasmid mediated heavy metal resistances in Enterobacter spp. isolated from Sofulu landfill 2005; 55(3): 175-9., 4Nies DH. Microbial heavy-metal resistance. Appl Microbiol Biotechnol 1999; 51(6): 730-50.[http://dx.doi.org/10.1007/s002530051457] [PMID: 10422221] ].

Mercury is the 16th rarest element on the earth [5Wedepohl KH. The composition of the continental crust. Geochim Cosmochim Acta 1995; 59(7): 1217-32.[http://dx.doi.org/10.1016/0016-7037(95)00038-2] ] and considered as one of the mobile and toxic metals that exist naturally in low concentrations in the environment, and can be changed between different forms. It is the only metal to be liquid at room temperature. It can also exist as gas due to its high vapor pressure [6Figueiredo NLL, Areias A, Mendes R, Canário J, Duarte A, Carvalho C. Mercury-resistant bacteria from salt marsh of Tagus Estuary: the influence of plants presence and mercury contamination levels. J Toxicol Environ Health A 2014; 77(14-16): 959-71.[http://dx.doi.org/10.1080/15287394.2014.911136] [PMID: 25072727] -8Dash HR, Das S. Bioremediation of mercury and the importance of bacterial mer genes. Int Biodeterior Biodegradation 2012; 75: 207-13.[http://dx.doi.org/10.1016/j.ibiod.2012.07.023] ].

It is a major environmental pollutant especially methylmercury (MeHg) form in the aquatic regions. It can accumulate in biota so can reach and affect both wildlife and human seriously. It is one of the environmentally stable and persistent toxins for long periods, also it can be accumulated in different biological tissues [9Keating MH, Beauregard D, Benjey WG, et al. Mercury Study Report to Congress Volume II: An Inventory of Anthropogenic Mercury Emissions in the United States. United States Environmental Protection Agency 1998. EPA-452/R-:1-181., 10Dash HR, Das S. International biodeterioration & biodegradation bioremediation of mercury and the importance of bacterial mer genes. Int Biodeterior Biodegradation 2012; 75: 207-13.[http://dx.doi.org/10.1016/j.ibiod.2012.07.023] ].

This review aims to cover all aspects related to the environmental biogeochemical cycle of mercury, the roles of mer genes in microbial adaptation to mercury, and potential bacterial remediation strategies of this toxic metal.

2. MERCURY BIOGEOCHEMICAL CYCLE

Environmental mercury cycle, as illustrated in Fig. (1), is usually facilitated biotically and abiotically between soils, water and atmosphere [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] ]. Mercury exists in the atmosphere in gaseous, particulates, and aqueous soluble forms [12Wang Q, Kim D, Dionysiou DD, Sorial Ga, Timberlake D. Sources and remediation for mercury contamination in aquatic systems - A literature review. Environ Pollut 2004; 131(2): 323-36.[http://dx.doi.org/10.1016/j.envpol.2004.01.010] [PMID: 15234099] ] but gaseous form represents about 95% of atmospheric mercury [13Smith T, Pitts K, McGarvey JA, Summers AO. Bacterial oxidation of mercury metal vapor, Hg(0). Appl Environ Microbiol 1998; 64(4): 1328-32.[PMID: 9546169] ] and it remains in the atmosphere for long periods. So, it can reach the far distance that should be considered as a huge environmental concern [12Wang Q, Kim D, Dionysiou DD, Sorial Ga, Timberlake D. Sources and remediation for mercury contamination in aquatic systems - A literature review. Environ Pollut 2004; 131(2): 323-36.[http://dx.doi.org/10.1016/j.envpol.2004.01.010] [PMID: 15234099] , 14Lindqvist O, Rodhe H. Atmospheric mercury—A review. Tellus B Chem Phys Meterol 1985; 37(3): 136-59.[http://dx.doi.org/10.3402/tellusb.v37i3.15010] , 15Keeler G, Glinsorn G, Pirrone N. Particulate mercury in the atmosphere: Its significance, transport, transformation and sources. Water Air Soil Pollut 1995; 80(1-4): 159-68.[http://dx.doi.org/10.1007/BF01189664] ].

2.1. Oxidation Processes

In the atmosphere, Hg0 abiotically oxidized to Hg+2 through photo-oxidation reactions, mediated by O2 through its interaction with hydrogen peroxide, ozone, sulfhydryl compounds, free radicals as Br, and by UV-B in presence of Cl2 and photoreactive compounds as benzoquinone in presence of water droplets [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 12Wang Q, Kim D, Dionysiou DD, Sorial Ga, Timberlake D. Sources and remediation for mercury contamination in aquatic systems - A literature review. Environ Pollut 2004; 131(2): 323-36.[http://dx.doi.org/10.1016/j.envpol.2004.01.010] [PMID: 15234099] , 16Munthe J, McElroy WJ. Some aqueous reactions of potential importance in the atmospheric chemistry of mercury. Atmos Environ Part A 1992; 26(4): 553-7.[http://dx.doi.org/10.1016/0960-1686(92)90168-K] ].

Fig. (1)
Environmental mercury biogeochemical cycle [10Dash HR, Das S. International biodeterioration & biodegradation bioremediation of mercury and the importance of bacterial mer genes. Int Biodeterior Biodegradation 2012; 75: 207-13.[http://dx.doi.org/10.1016/j.ibiod.2012.07.023] ].


Biotic Hg0 oxidation (bio-oxidation) in aerobic and phototrophic microorganisms is catalyzed by hydroperoxidases, katG and katE [13Smith T, Pitts K, McGarvey JA, Summers AO. Bacterial oxidation of mercury metal vapor, Hg(0). Appl Environ Microbiol 1998; 64(4): 1328-32.[PMID: 9546169] ] or other oxidases [17Matthew J, Colomboa JH, John R. Reinfeldera, Tamar Barkayb, Nathan Yeea. Anaerobic oxidation of Hg(0) and methylmercury formation by desulfovibrio desulfuricans ND132. Geochim Cosmochim Acta 2013; 112: 166-77.[http://dx.doi.org/10.1016/j.gca.2013.03.001] ]. Algae, plants and animals catalase and peroxidases are also capable of oxidizing Hg0 [17Matthew J, Colomboa JH, John R. Reinfeldera, Tamar Barkayb, Nathan Yeea. Anaerobic oxidation of Hg(0) and methylmercury formation by desulfovibrio desulfuricans ND132. Geochim Cosmochim Acta 2013; 112: 166-77.[http://dx.doi.org/10.1016/j.gca.2013.03.001] -19Colombo MJ, Ha J, Reinfelder JR, Barkay T, Yee N. Oxidation of Hg(0) to Hg(II) by diverse anaerobic bacteria. Chem Geol 2014; 363: 334-40.[http://dx.doi.org/10.1016/j.chemgeo.2013.11.020] ].

Anaerobic Hg0 oxidation mechanism by Desulfovibrio desulfuricans ND132 bacteria is unknown as obligate anaerobes do not carry such catalase or peroxidase genes but Colombo, Ha et al. 2013 suggested an alternative oxidation pathway influenced by reactive functional thiol groups of different anaerobic bacteria [17Matthew J, Colomboa JH, John R. Reinfeldera, Tamar Barkayb, Nathan Yeea. Anaerobic oxidation of Hg(0) and methylmercury formation by desulfovibrio desulfuricans ND132. Geochim Cosmochim Acta 2013; 112: 166-77.[http://dx.doi.org/10.1016/j.gca.2013.03.001] , 19Colombo MJ, Ha J, Reinfelder JR, Barkay T, Yee N. Oxidation of Hg(0) to Hg(II) by diverse anaerobic bacteria. Chem Geol 2014; 363: 334-40.[http://dx.doi.org/10.1016/j.chemgeo.2013.11.020] ] consistent with previous studies in which thiol moiety of organic compounds such as glutathione [20Zheng W, Liang L, Gu B. Mercury reduction and oxidation by reduced natural organic matter in anoxic environments. Environ Sci Technol 2012; 46(1): 292-9.[http://dx.doi.org/10.1021/es203402p] [PMID: 22107154] ] and reduced humic acid [21Gu B, Bian Y, Miller CL, Dong W, Jiang X, Liang L. Mercury reduction and complexation by natural organic matter in anoxic environments. Proc Natl Acad Sci USA 2011; 108(4): 1479-83.[http://dx.doi.org/10.1073/pnas.1008747108] [PMID: 21220311] ] can bind and oxidize Hg0.

2.2. Reduction Processes

Biotic Hg+2 reduction to Hg0 occurs by bacterial mercuric reductase enzyme encoded by merA gene on mer operon (described later) [8Dash HR, Das S. Bioremediation of mercury and the importance of bacterial mer genes. Int Biodeterior Biodegradation 2012; 75: 207-13.[http://dx.doi.org/10.1016/j.ibiod.2012.07.023] , 11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 22Hamlett NV, Landale EC, Davis BH, Summers AO. Roles of the Tn21 merT, merP, and merC gene products in mercury resistance and mercury binding. J Bacteriol 1992; 174(20): 6377-85.[http://dx.doi.org/10.1128/jb.174.20.6377-6385.1992] [PMID: 1328156] ], anaerobic Geobacter sulfurreducens PCA, Geothrix fermentans H5, Cupriavidus metallidurans AE104, Shenwella oneidensis MR-1 and Geobacter metallireducens GS-15 was found to reduce Hg+2 to Hg0 independent on the mer system but its need an electron acceptors and electron donors to suggest activity of respiratory electron transport chains. Its activity is effective at too low Hg+2 concentrations compared to amounts required for mer operon induction. Anaerobic bacteria showed dual role in the Hg redox cycle by both oxidizing Hg0 and reducing Hg+2 by unidentified reduction system other than mer system [19Colombo MJ, Ha J, Reinfelder JR, Barkay T, Yee N. Oxidation of Hg(0) to Hg(II) by diverse anaerobic bacteria. Chem Geol 2014; 363: 334-40.[http://dx.doi.org/10.1016/j.chemgeo.2013.11.020] , 22Hamlett NV, Landale EC, Davis BH, Summers AO. Roles of the Tn21 merT, merP, and merC gene products in mercury resistance and mercury binding. J Bacteriol 1992; 174(20): 6377-85.[http://dx.doi.org/10.1128/jb.174.20.6377-6385.1992] [PMID: 1328156] ].

The abiotic Hg+2 reduction is done not only by photochemical reactions but also via dark reactions [23Erie L. Mechanistic steps in the photoreduction of mercury in natural waters. 1994; 9697(1993).] using organic matter free radicals as fulvic [24Skogerboe RK, Wilson SA. Reduction of ionic species by fulvic acid. Anal Chem 1981; 53(2): 228-32.[http://dx.doi.org/10.1021/ac00225a023] ] and humic acid-associated free radicals [18Allard B, Arsenie I. Abiotic reduction of mercury by humic substances in aquatic system — An important process for the mercury cycle. Water Air Soil Pollut 1991; 56(1): 457-64.[http://dx.doi.org/10.1007/BF00342291] ].

2.3. Methylation Process

Biotic Hg+2 methylation is a natural bacterial process mainly occurred in seawater and coastal environment sediments [252013.], invertebrate digestive tracts, thawing permafrost soils, and extreme environments [26Podar M, Gilmour CC, Brandt CC, et al. Global prevalence and distribution of genes and microorganisms involved in mercury methylation. Sci Adv 2015; 1(9): e1500675.[http://dx.doi.org/10.1126/sciadv.1500675] [PMID: 26601305] ] through anaerobic methylators as Sulfate-Reducing Bacteria (SRB) [27Parks JM, Johs A, Podar M, et al. The genetic basis for bacterial mercury methylation. Science 2013; 339(6125): 1332-5.[http://dx.doi.org/10.1126/science.1230667] [PMID: 23393089] -30Choi SC, Chase T, Bartha R. Metabolic pathways leading to mercury methylation in Desulfovibrio desulfuricans LS. Appl Environ Microbiol 1994; 60(11): 4072-7.[PMID: 16349435] ], Iron Reducing Bacteria (IRB) and methanogens [27Parks JM, Johs A, Podar M, et al. The genetic basis for bacterial mercury methylation. Science 2013; 339(6125): 1332-5.[http://dx.doi.org/10.1126/science.1230667] [PMID: 23393089] , 31Hamelin S, Amyot M, Barkay T, Wang Y, Planas D. Methanogens: Principal methylators of mercury in lake periphyton. Environ Sci Technol 2011; 45(18): 7693-700.[http://dx.doi.org/10.1021/es2010072] [PMID: 21875053] , 32Kerin EJ, Gilmour CC, Roden E, Suzuki MT, Coates JD, Mason RP. Mercury methylation by dissimilatory iron-reducing bacteria. Appl Environ Microbiol 2006; 72(12): 7919-21.[http://dx.doi.org/10.1128/AEM.01602-06] [PMID: 17056699] ]. Two-gene cluster, hgcA and hgcB encode a putative corrinoid protein facilitating methyl transfer and a ferredoxin carrying out corrinoid reduction, were reported to be involved in mercury methylation process [27Parks JM, Johs A, Podar M, et al. The genetic basis for bacterial mercury methylation. Science 2013; 339(6125): 1332-5.[http://dx.doi.org/10.1126/science.1230667] [PMID: 23393089] ]. According to Podar et al. 2015, hgcA and hgcB genes were found in nearly all anaerobic environments but not in aerobic and not in human and mammalian microbiomes, reducing the expected risk of Hg methylation by microbiomes [26Podar M, Gilmour CC, Brandt CC, et al. Global prevalence and distribution of genes and microorganisms involved in mercury methylation. Sci Adv 2015; 1(9): e1500675.[http://dx.doi.org/10.1126/sciadv.1500675] [PMID: 26601305] ].

Another unrecognized oxidation/methylation pathway in the mercury cycle by anaerobic bacteria as in D. desulfuricans ND132 and G. sulphurreducens PCA [17Matthew J, Colomboa JH, John R. Reinfeldera, Tamar Barkayb, Nathan Yeea. Anaerobic oxidation of Hg(0) and methylmercury formation by desulfovibrio desulfuricans ND132. Geochim Cosmochim Acta 2013; 112: 166-77.[http://dx.doi.org/10.1016/j.gca.2013.03.001] , 33Hu H, Lin H, Zheng W, et al. Oxidation and methylation of dissolved elemental mercury by anaerobic bacteria. Nat Geosci 2013; 6(9): 751-4.[http://dx.doi.org/10.1038/ngeo1894] ] produces MeHg using dissolved Hg0 as their sole Hg source. Further investigation is required for detecting the reactions involved in and the connection between Hg methylation, oxidation and produced toxic MeHg exportation out of cells as D. desulfuricans lacks the mer operon system that detoxifies organic/inorganic mercury [17Matthew J, Colomboa JH, John R. Reinfeldera, Tamar Barkayb, Nathan Yeea. Anaerobic oxidation of Hg(0) and methylmercury formation by desulfovibrio desulfuricans ND132. Geochim Cosmochim Acta 2013; 112: 166-77.[http://dx.doi.org/10.1016/j.gca.2013.03.001] ].

Moreover, abiotic Hg+2 methylation carried out chemically [34Li Y, Cai Y. Progress in the study of mercury methylation and demethylation in aquatic environments. Chin Sci Bull 2013; 58(2): 177-85.[http://dx.doi.org/10.1007/s11434-012-5416-4] ] with the help of humic and fulvic acids, carboxylic acids, and compounds as fungicides or antifouling agents [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 35Cerrati G, Bernhard M, Weber JH. Model reactions for abiotic mercury (II) methylation: Kinetics of methylation of mercury (II) by mono‐, di‐, and tri‐methyltin in seawater. Appl Organomet Chem 1992; 6(7): 587-95.[http://dx.doi.org/10.1002/aoc.590060705] ]. It was found that sunlight played a minor and slower role in methylation reaction [36Li Y, Yin Y, Liu G, et al. Estimation of the major source and sink of methylmercury in the Florida Everglades. Environ Sci Technol 2012; 46(11): 5885-93.[http://dx.doi.org/10.1021/es204410x] [PMID: 22536798] ].

2.4. Demethylation Process

Biotic demethylation occurs simultaneously in the methylation sites as a reverse process [34Li Y, Cai Y. Progress in the study of mercury methylation and demethylation in aquatic environments. Chin Sci Bull 2013; 58(2): 177-85.[http://dx.doi.org/10.1007/s11434-012-5416-4] ]. It is catalyzed through reduction [37Begley TP, Walts AE, Walsh CT. Bacterial organomercurial Lyase: Over production, Isolation, and char acterization? 1986(1982); 7186-92.] or oxidation processes [38Oremland RS, Culbertson CW, Winfrey MR. Methylmercury decomposition in sediments and bacterial cultures: Involvement of methanogens and sulfate reducers in oxidative demethylation. Appl Environ Microbiol 1991; 57(1): 130-7.[PMID: 16348388] ]. Aerobic reductive demethylation of CH3Hg+ occurs through mer operon functions (merA and merB) forming CH4 and Hg0 [37Begley TP, Walts AE, Walsh CT. Bacterial organomercurial Lyase: Over production, Isolation, and char acterization? 1986(1982); 7186-92.]. Formed Hg0 will be evaporated into the air, and the cycle is repeated [39Schaefer JK, Letowski J, Barkay T. mer-mediated resistance and volatilization of Hg (II) under anaerobic conditions. Geomicrobiol J 2002; 19(1): 87-102.[http://dx.doi.org/10.1080/014904502317246192] , 40Summers AO, Silver S. Mercury resistance in a plasmid-bearing strain of Escherichia coli. J Bacteriol 1972; 112(3): 1228-36.[PMID: 4565536] ]. Anaerobic reductive demethylation, Geobacter bemidjiensis Bem is an iron-reducing bacterium capable of simultaneously both methylating Hg+2 and degrading MeHg, due to the the presence of homologues of an organomercurial lyase and a mercuric reductase [41Lu X, Liu Y, Johs A, et al. Anaerobic mercury methylation and demethylation by geobacter bemidjiensis Bem. Environ Sci Technol 2016; 50(8): 4366-73.[http://dx.doi.org/10.1021/acs.est.6b00401] [PMID: 27019098] ]. Oxidative demethylation occurs in more anaerobic conditions yielding CO2 and small amounts of Hg+2 with an unknown mechanism [38Oremland RS, Culbertson CW, Winfrey MR. Methylmercury decomposition in sediments and bacterial cultures: Involvement of methanogens and sulfate reducers in oxidative demethylation. Appl Environ Microbiol 1991; 57(1): 130-7.[PMID: 16348388] , 39Schaefer JK, Letowski J, Barkay T. mer-mediated resistance and volatilization of Hg (II) under anaerobic conditions. Geomicrobiol J 2002; 19(1): 87-102.[http://dx.doi.org/10.1080/014904502317246192] ]. Produced Hg+2 may be available for re-methylation process or reduction to its vapor form [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] ]. Both anaerobic methylation and demethylation processes are affected by environmental dissolved organic matter, iron-sulfate biogeochemistry, and Hg+2 concentration [17Matthew J, Colomboa JH, John R. Reinfeldera, Tamar Barkayb, Nathan Yeea. Anaerobic oxidation of Hg(0) and methylmercury formation by desulfovibrio desulfuricans ND132. Geochim Cosmochim Acta 2013; 112: 166-77.[http://dx.doi.org/10.1016/j.gca.2013.03.001] , 27Parks JM, Johs A, Podar M, et al. The genetic basis for bacterial mercury methylation. Science 2013; 339(6125): 1332-5.[http://dx.doi.org/10.1126/science.1230667] [PMID: 23393089] , 42Tjerngren I, Karlsson T, Björn E, Skyllberg U. Potential Hg methylation and MeHg demethylation rates related to the nutrient status of different boreal wetlands. Biogeochem 2012; 108(1): 335-50.[http://dx.doi.org/10.1007/s10533-011-9603-1] ].

Abiotic demethylation of MeHg affected by photo-degradation, especially UV-A and UV-B, at a wavelength range of 200-400 nm [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 43Suda I, Suda M, Hirayama K. Degradation of methyl and ethyl mercury by singlet oxygen generated from sea water exposed to sunlight or ultraviolet light. Arch Toxicol 1993; 67(5): 365-8.[http://dx.doi.org/10.1007/BF01973709] [PMID: 8368946] , 44Seller P, Kelly CA, Rudd JWM, MacHutchon AR. Photodegradation of methylmercury in lakes. Nature 1996; 380(6576): 694-7.[http://dx.doi.org/10.1038/380694a0] ]. A study on Hg cycling found that dissolved MeHg concentration was decreased in daylight and increased in non-daylight suggesting that photo-degradation in water has a major role in methylation/demethylation processes aquatic systems [45Naftz DL, Cederberg JR, Krabbenhoft DP, Beisner KR, Whitehead J, Gardberg J. Diurnal trends in methylmercury concentration in a wetland adjacent to Great Salt Lake, Utah, USA. Chem Geol 2011; 283(1-2): 78-86.[http://dx.doi.org/10.1016/j.chemgeo.2011.02.005] ].

All mercury forms (Hg0, Hg+2, and CH3Hg+) are interconvertible and can be introduced into the aquatic system [8Dash HR, Das S. Bioremediation of mercury and the importance of bacterial mer genes. Int Biodeterior Biodegradation 2012; 75: 207-13.[http://dx.doi.org/10.1016/j.ibiod.2012.07.023] ]. Their concentration in the aquatic system depends mainly on reduction, methylation, and demethylation ratio which depend on the microbial community [6Figueiredo NLL, Areias A, Mendes R, Canário J, Duarte A, Carvalho C. Mercury-resistant bacteria from salt marsh of Tagus Estuary: the influence of plants presence and mercury contamination levels. J Toxicol Environ Health A 2014; 77(14-16): 959-71.[http://dx.doi.org/10.1080/15287394.2014.911136] [PMID: 25072727] ].

CH3Hg+ had a different pathway as bio-accumulator in the food chain. Its concentration is higher in top food chain organisms due to CH3Hg+ biomagnifications [46Nascimento AM, Chartone-Souza E. Operon mer: Bacterial resistance to mercury and potential for bioremediation of contaminated environments. Genet Mol Res 2003; 2(1): 92-101.[PMID: 12917805] ]. As CH3Hg+ concentration is higher in predatory animals such as beluga and polar bears than marine mammals which have higher concentrations of Hg than freshwater fish and overland mammals, due to their higher position in marine food webs [47Braune B, Chételat J, Amyot M, et al. Mercury in the marine environment of the Canadian Arctic: review of recent findings. Sci Total Environ 2015; 509-510: 67-90.[http://dx.doi.org/10.1016/j.scitotenv.2014.05.133] [PMID: 24953756] ]. Marine and freshwater fishes are still the main sources of dietary Hg exposure for humans [6Figueiredo NLL, Areias A, Mendes R, Canário J, Duarte A, Carvalho C. Mercury-resistant bacteria from salt marsh of Tagus Estuary: the influence of plants presence and mercury contamination levels. J Toxicol Environ Health A 2014; 77(14-16): 959-71.[http://dx.doi.org/10.1080/15287394.2014.911136] [PMID: 25072727] , 47Braune B, Chételat J, Amyot M, et al. Mercury in the marine environment of the Canadian Arctic: review of recent findings. Sci Total Environ 2015; 509-510: 67-90.[http://dx.doi.org/10.1016/j.scitotenv.2014.05.133] [PMID: 24953756] ]. CH3Hg+ is the main specie absorbed in the gut; it enters the bloodstream and distributes to body tissues and organs [47Braune B, Chételat J, Amyot M, et al. Mercury in the marine environment of the Canadian Arctic: review of recent findings. Sci Total Environ 2015; 509-510: 67-90.[http://dx.doi.org/10.1016/j.scitotenv.2014.05.133] [PMID: 24953756] ]. In fish, CH3Hg+ first accumulates in the viscera (kidney, spleen, and liver) and later redistributed to other tissues as muscles and brain tissues. Hence, mammals and birds can demethylate CH3Hg+. So, a large amount of accumulated Hg in liver and kidney are found in an inorganic form [47Braune B, Chételat J, Amyot M, et al. Mercury in the marine environment of the Canadian Arctic: review of recent findings. Sci Total Environ 2015; 509-510: 67-90.[http://dx.doi.org/10.1016/j.scitotenv.2014.05.133] [PMID: 24953756] ].

3. MERCURY BIOREMEDIATION

It is a remediation technique using a wide range of living organisms (algae, fungi, yeasts, plants and bacteria) or their enzymes. Bioremediation is preferred as environmental friendly, promising technique. Microbial remediation using bacteria is widely used as they can be easily cultivated, grow faster and can accumulate metals in different conditions [48Dixit R, Wasiullah EY, Malaviya D, et al. Bioremediation of heavy metals from soil and aquatic environment: An overview of principles and criteria of fundamental processes. Sustainability 2015; 7(2): 2189-212.[http://dx.doi.org/10.3390/su7022189] -51McCarthy D, Edwards GC, Gustin MS, Care A, Miller MB, Sunna A. An innovative approach to bioremediation of mercury contaminated soils from industrial mining operations. Chemosphere 2017; 184: 694-9.[http://dx.doi.org/10.1016/j.chemosphere.2017.06.051] [PMID: 28633064] ]. Moreover, different Gram-negative and positive bacterial isolates can resist, accumulate, adsorb and transform toxic mercury forms to less toxic forms by different mechanisms. These bacteria are named Mercury Resistant Bacteria (MRB) [8Dash HR, Das S. Bioremediation of mercury and the importance of bacterial mer genes. Int Biodeterior Biodegradation 2012; 75: 207-13.[http://dx.doi.org/10.1016/j.ibiod.2012.07.023] , 12Wang Q, Kim D, Dionysiou DD, Sorial Ga, Timberlake D. Sources and remediation for mercury contamination in aquatic systems - A literature review. Environ Pollut 2004; 131(2): 323-36.[http://dx.doi.org/10.1016/j.envpol.2004.01.010] [PMID: 15234099] , 48Dixit R, Wasiullah EY, Malaviya D, et al. Bioremediation of heavy metals from soil and aquatic environment: An overview of principles and criteria of fundamental processes. Sustainability 2015; 7(2): 2189-212.[http://dx.doi.org/10.3390/su7022189] ]. Bioremediation using bacterial strains showed promising results, reached 76.4% compared to other remediation techniques in removing mercury pollutant leached from spent fluorescent lamps [52Elekes CC, Busuioc G. The mycoremediation of metals polluted soils using wild growing species of mushrooms. 2010; Jul 22; 2010; pp. In: In Proceedings of the 7th WSEAS international conference on Latest trands on Eng Educ, Corfu Island Greece 2010; 36-9.].

3.1. Phytoremediation

Green plants or its associated microorganisms are used to remove or destroy contaminants from the soil. The insertion of bacterial mercury resistance genes as (merP, merC, merF and merT) encodes for different transporter proteins, (merA) encodes for mercury reductase or (merB) encodes for organomercurial lyase into plant cells after their sequences modification according to preferred plant codons. Genes inserted as merB remove organic mercury by protonolysis of C-Hg to Hg+2 while merA helps in the reduction of Hg+2 by the formation of volatile elemental mercury Hg0 which is then volatilized out of plant cells [53Wang J, Feng X, Anderson CWN, Xing Y, Shang L. Remediation of mercury contaminated sites - A review. J Hazard Mater 2012; 221-222: 1-18.[http://dx.doi.org/10.1016/j.jhazmat.2012.04.035] [PMID: 22579459] -57Bizily SP, Rugh CL, Summers AO, Meagher RB. Phytoremediation of methylmercury pollution: merB expression in Arabidopsis thaliana confers resistance to organomercurials. Proc Natl Acad Sci USA 1999; 96(12): 6808-13.[http://dx.doi.org/10.1073/pnas.96.12.6808] [PMID: 10359794] ]. Different plant types and species were engineered as Arabidopsis thaliana as described in Table 1, yellow poplar [58Rugh CL, Senecoff JF, Meagher RB, Merkle SA. Development of transgenic yellow poplar for mercury phytoremediation. Nat Biotechnol 1998; 16(10): 925-8.[http://dx.doi.org/10.1038/nbt1098-925] [PMID: 9788347] ], tobacco [59He YK, Sun JG, Feng XZ, Czakó M, Márton L. Differential mercury volatilization by tobacco organs expressing a modified bacterial merA gene. Cell Res 2001; 11(3): 231-6.[http://dx.doi.org/10.1038/sj.cr.7290091] [PMID: 11642409] , 60Ruiz ON, Hussein HS, Terry N, Daniell H. Phytoremediation of organomercurial compounds via chloroplast genetic engineering. Plant Physiol 2003; 132(3): 1344-52.[http://dx.doi.org/10.1104/pp.103.020958] [PMID: 12857816] ], peanut [61Yang H, Nairn J, Ozias-Akins P, Ozias-akins P. Transformation of peanut using a modified bacterial mercuric ion reductase gene driven by an actin promoter from Arabidopsis thaliana. J Plant Physiol 2003; 160(8): 945-52.[http://dx.doi.org/10.1078/0176-1617-01087] [PMID: 12964870] ], salt marsh cordgrass [62Czakó M, Feng X, He Y, Liang D, Márton L. Transgenic Spartina alterniflora for phytoremediation. Environ Geochem Health 2006; 28(1-2): 103-10.[http://dx.doi.org/10.1007/s10653-005-9019-8] [PMID: 16528587] ], rice [63Heaton AC, Rugh CL, Kim T, Wang NJ, Meagher RB. Toward detoxifying mercury-polluted aquatic sediments with rice genetically engineered for mercury resistance. Environ Toxicol Chem 2003; 22(12): 2940-7.[http://dx.doi.org/10.1897/02-442] [PMID: 14713034] ] and eastern cottonwood [64Che D, Meagher RB, Heaton AC, Lima A, Rugh CL, Merkle SA. Expression of mercuric ion reductase in Eastern cottonwood (Populus deltoides) confers mercuric ion reduction and resistance. Plant Biotechnol J 2003; 1(4): 311-9.[http://dx.doi.org/10.1046/j.1467-7652.2003.00031.x] [PMID: 17163907] , 65Lyyra S, Meagher RB, Kim T, et al. Coupling two mercury resistance genes in Eastern cottonwood enhances the processing of organomercury. Plant Biotechnol J 2007; 5(2): 254-62.[http://dx.doi.org/10.1111/j.1467-7652.2006.00236.x] [PMID: 17309680] ] that showed successful high resistance levels than their wild types.

Hence, genetically engineered plants can get rid of ionic and organic mercury by phytovolatilization. However, phytovolatilization major concern is the release of mercury vapors back to the environment, but this can be reduced by increasing efficacy of phytoextraction/phytosequestration. This could be achieved by transforming plants with certain bacterial genes as merP, merC, merF and merT [53Wang J, Feng X, Anderson CWN, Xing Y, Shang L. Remediation of mercury contaminated sites - A review. J Hazard Mater 2012; 221-222: 1-18.[http://dx.doi.org/10.1016/j.jhazmat.2012.04.035] [PMID: 22579459] ]. For example, the increase of Hg+2 bioaccumulation in transgenic tobacco by expressions of the merP gene producing bacterial Polyphosphate Kinase (PPK) [54Ruiz ON, Daniell H. Genetic engineering to enhance mercury phytoremediation. Curr Opin Biotechnol 2009; 20(2): 213-9.[http://dx.doi.org/10.1016/j.copbio.2009.02.010] [PMID: 19328673] , 66Nagata T, Ishikawa C, Kiyono M, Pan-Hou H. Accumulation of mercury in transgenic tobacco expressing bacterial polyphosphate. Biol Pharm Bull 2006; 29(12): 2350-3.[http://dx.doi.org/10.1248/bpb.29.2350] [PMID: 17142961] ].

An MRB Enterobacter strain exhibited a novel property of Hg immobilization by synthesis of nanoparticle Hg. The strain could intracellularly synthesize Hg nano-particles sized 2–5-nm [67Sinha A, Khare SK. Mercury bioaccumulation and simultaneous nanoparticle synthesis by Enterobacter sp. cells. Bioresour Technol 2011; 102(5): 4281-4.[http://dx.doi.org/10.1016/j.biortech.2010.12.040] [PMID: 21216593] ].

Table 1
Effect of different mer genes, inserted and expressed in different regions of A. thaliana plant, on mercury phytoremediation.


4. MERCURY RESISTANCE MECHANISMS

To adapt to toxic metals in the environment, bacteria and other organisms have developed different resistance mechanisms as a defense systems against these toxic materials. This defense systems that help bacteria to eliminate toxic materials from their growth medium includes:

  1. Mercury bioaccumulation whether by simultaneous synthesis of mercury as nanoparticles [67Sinha A, Khare SK. Mercury bioaccumulation and simultaneous nanoparticle synthesis by Enterobacter sp. cells. Bioresour Technol 2011; 102(5): 4281-4.[http://dx.doi.org/10.1016/j.biortech.2010.12.040] [PMID: 21216593] ] or by Hg+2 binding to carboxyl phosphates, hydroxyl, thio, or pyridine functional groups located on some bacterial cell wall [49Deng X, Wang P. Isolation of marine bacteria highly resistant to mercury and their bioaccumulation process. Bioresour Technol 2012; 121: 342-7.[http://dx.doi.org/10.1016/j.biortech.2012.07.017] [PMID: 22864169] ] so, mercury is trapped and can’t be vaporized back into the environment [67Sinha A, Khare SK. Mercury bioaccumulation and simultaneous nanoparticle synthesis by Enterobacter sp. cells. Bioresour Technol 2011; 102(5): 4281-4.[http://dx.doi.org/10.1016/j.biortech.2010.12.040] [PMID: 21216593] ],
  2. Sequestration and chelation of mercury using intracellular binding Metallothionein protein [68Kretsinger RH, Uversky VN, Permyakov EA. Encyclopedia of Metalloproteins 2013.[http://dx.doi.org/10.1007/978-1-4614-1533-6] ], a cysteine-rich protein able to bind mercury ions to form Mercury-cysteine complexion or extracellular polysaccharides in the cell wall [69Baldi F, Pepi M, Filippelli M. Methylmercury resistance in desulfovibrio desulfuricans strains in relation to methylmercury degradation. Appl Environ Microbiol 1993; 59(8): 2479-85.[PMID: 16349013] , 70Bhakta V, Balkrishna M, Thakuri C. Bacterial mer operon-mediated detoxification of mercurial compounds: Ashort review. Arch Microbiol 2011; 837-44.] as mercury compounds have high ability to bind with thiols of bacterial cysteine and reduce mercury toxicities [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] ],
  3. Blocking mercury entry into cells through permeability barriers [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 71Pan-Hou HS, Nishimoto M, Imura N. Possible role of membrane proteins in mercury resistance of Enterobacter aerogenes. Arch Microbiol 1981; 130(2): 93-5.[http://dx.doi.org/10.1007/BF00411057] [PMID: 6459062] ],
  4. Efflux and volatilization to convert toxic ionic mercury, Hg+2, to much less toxic, elemental mercury, Hg0 through genetic manner [70Bhakta V, Balkrishna M, Thakuri C. Bacterial mer operon-mediated detoxification of mercurial compounds: Ashort review. Arch Microbiol 2011; 837-44.], reductase enzymes as those expressed by the help of mercury resistance (mer) operon that will be described later [3Nisa M, Coral Ü, Korkmaz H, Arikan B, Coral G. Plasmid mediated heavy metal resistances in Enterobacter spp. isolated from Sofulu landfill 2005; 55(3): 175-9., 70Bhakta V, Balkrishna M, Thakuri C. Bacterial mer operon-mediated detoxification of mercurial compounds: Ashort review. Arch Microbiol 2011; 837-44., 72Dash HR, Das S. Bioremediation of mercury and the importance of bacterial mer genes. Int Biodeterior Biodegradation 2012; 75: 207-13.[http://dx.doi.org/10.1016/j.ibiod.2012.07.023] ] or through cytochrome c oxidase enzymes [73Sugio T, Komoda T, Okazaki Y, Takeda Y, Nakamura S, Takeuchi F. Volatilization of metal mercury from Organomercurials by highly mercury-resistant Acidithiobacillus ferrooxidans MON-1. Biosci Biotechnol Biochem 2010; 74(5): 1007-12.[http://dx.doi.org/10.1271/bbb.90888] [PMID: 20460735] ].

For these valuable mechanisms, different bacterial strains and other biological systems were engineered to be used for remediation and monitoring of environmental hazards such as increasing the bioaccumulation of Hg+2 by expression of the bacterial Polyphosphate Kinase (PPK) in transgenic tobacco [66Nagata T, Ishikawa C, Kiyono M, Pan-Hou H. Accumulation of mercury in transgenic tobacco expressing bacterial polyphosphate. Biol Pharm Bull 2006; 29(12): 2350-3.[http://dx.doi.org/10.1248/bpb.29.2350] [PMID: 17142961] ].

5. COMPONENTS AND FUNCTIONS OF MER OPERON IN MERCURY RESISTANT BACTERIA (MRB)

All mer determinants (mer operon) are widely distributed by both Horizontal (HGT) and Vertical Gene Transfer (VGT) which explain their presence in different bacterial populations [70Bhakta V, Balkrishna M, Thakuri C. Bacterial mer operon-mediated detoxification of mercurial compounds: Ashort review. Arch Microbiol 2011; 837-44.]. It was found located on chromosomal DNA [74Zeng XX, Tagn JX, Jiang P, Liu H W, Dai Z-mM, Liu X-dD. Isolation, characterization and extraction of mer gene of Hg2+ resisting strain D2. Trans Nonferrous Met Soc China 2010; 20(50621063): 507-12. [English Edition].[http://dx.doi.org/10.1016/S1003-6326(09)60170-9] ], mobile elements as plasmids [40Summers AO, Silver S. Mercury resistance in a plasmid-bearing strain of Escherichia coli. J Bacteriol 1972; 112(3): 1228-36.[PMID: 4565536] , 75Schelert J, Dixit V, Hoang V, Simbahan J, Drozda M, Blum P. Occurrence and characterization of mercury resistance in the hyperthermophilic archaeon Sulfolobus solfataricus by use of gene disruption. J Bacteriol 2004; 186(2): 427-37.[http://dx.doi.org/10.1128/JB.186.2.427-437.2004] [PMID: 14702312] ], transposons as components of the Tn21 [22Hamlett NV, Landale EC, Davis BH, Summers AO. Roles of the Tn21 merT, merP, and merC gene products in mercury resistance and mercury binding. J Bacteriol 1992; 174(20): 6377-85.[http://dx.doi.org/10.1128/jb.174.20.6377-6385.1992] [PMID: 1328156] , 76Liebert CA, Hall RM, Summers AO. Transposon Tn21, flagship of the floating genome. Microbiol Mol Biol Rev 1999; 63(3): 507-22.[PMID: 10477306] ] and Tn501 [46Nascimento AM, Chartone-Souza E. Operon mer: Bacterial resistance to mercury and potential for bioremediation of contaminated environments. Genet Mol Res 2003; 2(1): 92-101.[PMID: 12917805] ], or on integrons [77Wireman J, Liebert CA, Smith T, et al. Association of mercury resistance with antibiotic resistance in the gram-negative fecal bacteria of primates. Association of Mercury Resistance with Antibiotic Resistance in the Gram-Negative Fecal Bacteria of Primates 1997; 63(11)]. These mer determinants were identified in a wide range of previously isolated gram-negative [78Pepi M, Gaggi C, Bernardini E, et al. Mercury-resistant bacterial strains Pseudomonas and Psychrobacter spp. isolated from sediments of Orbetello Lagoon (Italy) and their possible use in bioremediation processes. Int Biodeterior Biodegradation 2011; 65(1): 85-91.[http://dx.doi.org/10.1016/j.ibiod.2010.09.006] ] as seen in Fig. (2) and Gram-positive [79Figueiredo NLL, Canário J, Duarte A, Serralheiro ML, Carvalho C. Isolation and characterization of mercury-resistant bacteria from sediments of Tagus Estuary (Portugal): Implications for environmental and human health risk assessment. J Toxicol Environ Health A 2014; 77(1-3): 155-68.[http://dx.doi.org/10.1080/15287394.2014.867204] [PMID: 24555656] ] bacterial strains from clinical [80D SR. Prevalence of Mercury-Resistant and Antibiotic-Resistant Bacteria found in Dental Amalgam. 2014; 3(4): 1-4., 81Summers AO, Wireman J, Vimy MJ, et al. Mercury released from dental “silver” fillings provokes an increase in mercury- and antibiotic-resistant bacteria in oral and intestinal floras of primates. Antimicrob Agents Chemother 1993; 37(4): 825-34.[http://dx.doi.org/10.1128/AAC.37.4.825] [PMID: 8280208] ] and environmental [82Ball MM, Carrero P, Castro D, Yarzábal LA. Mercury resistance in bacterial strains isolated from tailing ponds in a gold mining area near El Callao (Bolívar State, Venezuela). Curr Microbiol 2007; 54(2): 149-54.[http://dx.doi.org/10.1007/s00284-006-0347-4] [PMID: 17200804] , 83François F, Lombard C, Guigner JM, et al. Isolation and characterization of environmental bacteria capable of extracellular biosorption of mercury. Appl Environ Microbiol 2012; 78(4): 1097-106.[http://dx.doi.org/10.1128/AEM.06522-11] [PMID: 22156431] ] samples. Genes in mer operon express different enzymes that can transform toxic to less toxic mercury forms as organomercuriallyase and mercuric reductase as illustrated in Table 2. In addition to mercury detoxification, some MRB can also detoxify other metals [84De J, Ramaiah N. Characterization of marine bacteria highly resistant to mercury exhibiting multiple resistances to toxic chemicals. Ecol Indic 2007; 7(3): 511-20.[http://dx.doi.org/10.1016/j.ecolind.2006.05.002] ].

These mer determinants are classified into two types; narrow-spectrum that detoxifies only inorganic mercury through the main merA gene or broad-spectrum that detoxifies both organic and inorganic mercury through merA and merB genes [8Dash HR, Das S. Bioremediation of mercury and the importance of bacterial mer genes. Int Biodeterior Biodegradation 2012; 75: 207-13.[http://dx.doi.org/10.1016/j.ibiod.2012.07.023] , 85Bogdanova ES, Bass IA, Minakhin LS, et al. Horizontal spread of mer operons among gram-positive bacteria in natural environments. Microbiology 1998; 144(Pt 3): 609-20.[http://dx.doi.org/10.1099/00221287-144-3-609] [PMID: 9534232] , 86Dash HR, Sahu M, Mallick B, Das S. Functional efficiency of MerA protein among diverse mercury resistant bacteria for efficient use in bioremediation of inorganic mercury. Biochimie 2017; 142: 207-15.[http://dx.doi.org/10.1016/j.biochi.2017.09.016] [PMID: 28966143] ]. The mer operon is composed of the operator, promoter, regulator genes, and functional genes such as merR, merP, merT, merD, merA, merF, merC, merE, merH, merG and merB. All these genes code for different proteins that participate in the detection, transportation and reduction or methylation of mercury ions [7Brooks S, Moore C, Lew D, Lefer B, Huey G, Tanner D. Temperature and sunlight controls of mercury oxidation and deposition atop the Greenland ice sheet. ‎. Atmos Chem Phys 2011; 11(16): 8295-306.[http://dx.doi.org/10.5194/acp-11-8295-2011] , 75Schelert J, Dixit V, Hoang V, Simbahan J, Drozda M, Blum P. Occurrence and characterization of mercury resistance in the hyperthermophilic archaeon Sulfolobus solfataricus by use of gene disruption. J Bacteriol 2004; 186(2): 427-37.[http://dx.doi.org/10.1128/JB.186.2.427-437.2004] [PMID: 14702312] , 87Yu Z, Li J, Li Y, et al. A mer operon confers mercury reduction in a Staphylococcus epidermidis strain isolated from Lanzhou reach of the Yellow River. Int Biodeterior Biodegradation 1981; 90: 57-63.[http://dx.doi.org/10.1016/j.ibiod.2014.02.002] , 88Naik MM, Dubey S. Lead-and mercury-resistant marine bacteria and their application in lead and mercury bioremediation Marine Pollution and Microbial Remediation 2017; 29-40.].

Table 2
All mer operon genes and their expressed proteins.


5.1. Hg+2 Binding and Transportation Genes

merT, merP, merC, merE, merF, and newly discovered merH express different proteins that have different roles in mercury transportation as shown in Fig. (2) [89Boyd ES, Barkay T. The mercury resistance operon: from an origin in a geothermal environment to an efficient detoxification machine. Front Microbiol 2012; 3: 349.[http://dx.doi.org/10.3389/fmicb.2012.00349] [PMID: 23087676] ].

merT, expresses an inner membrane (cytoplasmic) proteins [22Hamlett NV, Landale EC, Davis BH, Summers AO. Roles of the Tn21 merT, merP, and merC gene products in mercury resistance and mercury binding. J Bacteriol 1992; 174(20): 6377-85.[http://dx.doi.org/10.1128/jb.174.20.6377-6385.1992] [PMID: 1328156] ], helps in the uptake of organic phenylmercury [90Sone Y, Nakamura R, Pan-hou H, Itoh T, Kiyono M. MerP in resistance to mercurials and the transport of mercurials in Escherichia coli. 2013; 36:1835-41.] and inorganic mercury transport into the cytoplasm [91Jan AT, Azam M, Ali A, Haq QMR. Molecular characterization of mercury resistant bacteria inhabiting polluted water bodies of different geographical locations in India. Curr Microbiol 2012; 65(1): 14-21.[http://dx.doi.org/10.1007/s00284-012-0118-3] [PMID: 22488489] ]. MerT protein has three transmembrane regions with cysteine pair located in its first transmembrane region Cys-Cys [90Sone Y, Nakamura R, Pan-hou H, Itoh T, Kiyono M. MerP in resistance to mercurials and the transport of mercurials in Escherichia coli. 2013; 36:1835-41.].

merP, expresses a periplasmic protein [22Hamlett NV, Landale EC, Davis BH, Summers AO. Roles of the Tn21 merT, merP, and merC gene products in mercury resistance and mercury binding. J Bacteriol 1992; 174(20): 6377-85.[http://dx.doi.org/10.1128/jb.174.20.6377-6385.1992] [PMID: 1328156] ] that has two cysteine residues to help in replacing the nucleophiles (Cl-) linked to Hg+2 so, Hg+2 could bind to merP cysteine residues then transferred to other two cysteine residues on merT protein located on cytoplasmic membrane [8Dash HR, Das S. Bioremediation of mercury and the importance of bacterial mer genes. Int Biodeterior Biodegradation 2012; 75: 207-13.[http://dx.doi.org/10.1016/j.ibiod.2012.07.023] , 11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 76Liebert CA, Hall RM, Summers AO. Transposon Tn21, flagship of the floating genome. Microbiol Mol Biol Rev 1999; 63(3): 507-22.[PMID: 10477306] ] then passed to other pair of merT’s cytosolic cysteines residues. Hg+2 enters the cytoplasmic membrane where cytosolic thiols (cysteines or glutathions) compete with merT’s cytosolic cysteines to bind with Hg+2 to be ready for merA activity [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] ].

merT and merP deletion from transposon Tn501 lead to Hg+2 sensitivity while the expression of Tn501 merT and merP in the absence of mercuric reductase causes Hg+2 supersensitivity [22Hamlett NV, Landale EC, Davis BH, Summers AO. Roles of the Tn21 merT, merP, and merC gene products in mercury resistance and mercury binding. J Bacteriol 1992; 174(20): 6377-85.[http://dx.doi.org/10.1128/jb.174.20.6377-6385.1992] [PMID: 1328156] ]. Moreover, mutations in both merT and merP increase Hg+2 concentration required for induction of merA-lacZ transcriptional fusions. So, merP is important for Hg+2 resistance [22Hamlett NV, Landale EC, Davis BH, Summers AO. Roles of the Tn21 merT, merP, and merC gene products in mercury resistance and mercury binding. J Bacteriol 1992; 174(20): 6377-85.[http://dx.doi.org/10.1128/jb.174.20.6377-6385.1992] [PMID: 1328156] ]. However, Sone and Nakamura et al. showed that absence of merP in presence of other alternative transporters merC, merE, merF and merT would increase both inorganic and organic mercury transportation. While the presence of merP with all other transporters did not cause any difference in organic mercury transportation but increased the inorganic transportation [90Sone Y, Nakamura R, Pan-hou H, Itoh T, Kiyono M. MerP in resistance to mercurials and the transport of mercurials in Escherichia coli. 2013; 36:1835-41.]. MerE, MerT, MerC and MerF are broad-spectrum mercury transporter proteins that can transport organic phenylmercury and inorganic Hg+2 into cells [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 90Sone Y, Nakamura R, Pan-hou H, Itoh T, Kiyono M. MerP in resistance to mercurials and the transport of mercurials in Escherichia coli. 2013; 36:1835-41.-92Wilson JR, Leang C, Morby AP, Hobman JL, Brown NL. MerF is a mercury transport protein: different structures but a common mechanism for mercuric ion transporters? FEBS Lett 2000; 472(1): 78-82.[http://dx.doi.org/10.1016/S0014-5793(00)01430-7] [PMID: 10781809] ].

MerC, expresses an inner membrane (cytoplasmic) protein [22Hamlett NV, Landale EC, Davis BH, Summers AO. Roles of the Tn21 merT, merP, and merC gene products in mercury resistance and mercury binding. J Bacteriol 1992; 174(20): 6377-85.[http://dx.doi.org/10.1128/jb.174.20.6377-6385.1992] [PMID: 1328156] ], that is involved in both inorganic and organic phenylmercury [90Sone Y, Nakamura R, Pan-hou H, Itoh T, Kiyono M. MerP in resistance to mercurials and the transport of mercurials in Escherichia coli. 2013; 36:1835-41.] uptake across the cytoplasmic membrane till it reaches active site reductase [70Bhakta V, Balkrishna M, Thakuri C. Bacterial mer operon-mediated detoxification of mercurial compounds: Ashort review. Arch Microbiol 2011; 837-44.]. MerC protein was found to have roles in mercury accumulation in Arabidopsis thaliana [93Kiyono M, Oka Y, Sone Y, et al. Bacterial heavy metal transporter MerC increases mercury accumulation in Arabidopsis thaliana. Biochem Eng J 2013; 71: 19-24.[http://dx.doi.org/10.1016/j.bej.2012.11.007] ].

Absence or mutation of merC could show no effects on mercury transportation and resistance in case of presence of merT and merP as shown in Tn501 and Tn5053. However, in some bacterial strains when both merT and merP do not exist, merC can act alone as the main Hg+2 transporter [22Hamlett NV, Landale EC, Davis BH, Summers AO. Roles of the Tn21 merT, merP, and merC gene products in mercury resistance and mercury binding. J Bacteriol 1992; 174(20): 6377-85.[http://dx.doi.org/10.1128/jb.174.20.6377-6385.1992] [PMID: 1328156] , 76Liebert CA, Hall RM, Summers AO. Transposon Tn21, flagship of the floating genome. Microbiol Mol Biol Rev 1999; 63(3): 507-22.[PMID: 10477306] ]. Other new findings showed that merC is more preferred in Hg+2 transportation than merE, merF and merT. Moreover, merC was more efficient for designing successful mercurial bioremediation system [90Sone Y, Nakamura R, Pan-hou H, Itoh T, Kiyono M. MerP in resistance to mercurials and the transport of mercurials in Escherichia coli. 2013; 36:1835-41.].

merF helps in both organic phenylmercury [90Sone Y, Nakamura R, Pan-hou H, Itoh T, Kiyono M. MerP in resistance to mercurials and the transport of mercurials in Escherichia coli. 2013; 36:1835-41.] and inorganic Hg+2 transport across the cytoplasm [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 92Wilson JR, Leang C, Morby AP, Hobman JL, Brown NL. MerF is a mercury transport protein: different structures but a common mechanism for mercuric ion transporters? FEBS Lett 2000; 472(1): 78-82.[http://dx.doi.org/10.1016/S0014-5793(00)01430-7] [PMID: 10781809] ].

merH expresses a membrane protein and according to Schué, it was able to transport Hg+2 across the inner membrane using its two cysteine residue. Replacing merT gene in an E-coli strain by merH resulted in Hg+2 MIC reduction, although the strain is still resistant when compared with a control strain which has no transporter proteins [94Schué M, Dover LG, Besra GS, Parkhill J, Brown NL. Sequence and analysis of a plasmid-encoded mercury resistance operon from Mycobacterium marinum identifies MerH, a new mercuric ion transporter. J Bacteriol 2009; 191(1): 439-44.[http://dx.doi.org/10.1128/JB.01063-08] [PMID: 18931130] ]. As described by Schelert, a metallochaperone, homolog to C-terminal domain, called TRASH has a role in metal sensing and trafficking that explains merH role in trafficking of Hg+2 to the MerR transcription factor. By non-sense or in-frame gene mutation of merH, the new mutant strain was highly sensitive to Hg+2 and analysis of merH deleted operon by mass spectroscopic. They found increased retention of Hg+2 intracellular that explains the low rate of mer operon induction and the need for merH in metal trafficking [95Schelert J, Rudrappa D, Johnson T, Blum P. Role of MerH in mercury resistance in the archaeon Sulfolobus solfataricus. Microbiology 2013; 159(Pt 6): 1198-208.[http://dx.doi.org/10.1099/mic.0.065854-0] [PMID: 23619003] ].

merE is involved in the transport system of inorganic [89Boyd ES, Barkay T. The mercury resistance operon: from an origin in a geothermal environment to an efficient detoxification machine. Front Microbiol 2012; 3: 349.[http://dx.doi.org/10.3389/fmicb.2012.00349] [PMID: 23087676] ] and organic phenylmercury compounds selectively across the membrane [96Kiyono M, Pan-Hou H. The merG gene product is involved in phenylmercury resistance in Pseudomonas strain K-62. J Bacteriol 1999; 181(3): 726-30.[PMID: 9922233] ]. Organomercurial compounds are lipid-soluble and can pass through the cell membrane by simple diffusion [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 97Osborn AM, Bruce KD, Strike P, Ritchie DA. Distribution, diversity and evolution of the bacterial mercury resistance (mer) operon. FEMS Microbiol Rev 1997; 19(4): 239-62.[http://dx.doi.org/10.1111/j.1574-6976.1997.tb00300.x] [PMID: 9167257] ] or are transported inside by merE or merG [98Das S, Dash HR, Chakraborty J. Genetic basis and importance of metal resistant genes in bacteria for bioremediation of contaminated environments with toxic metal pollutants. Appl Microbiol Biotechnol 2016; 100(7): 2967-84.[http://dx.doi.org/10.1007/s00253-016-7364-4] [PMID: 26860944] ]. Their transport system is poorly understood [96Kiyono M, Pan-Hou H. The merG gene product is involved in phenylmercury resistance in Pseudomonas strain K-62. J Bacteriol 1999; 181(3): 726-30.[PMID: 9922233] , 97Osborn AM, Bruce KD, Strike P, Ritchie DA. Distribution, diversity and evolution of the bacterial mercury resistance (mer) operon. FEMS Microbiol Rev 1997; 19(4): 239-62.[http://dx.doi.org/10.1111/j.1574-6976.1997.tb00300.x] [PMID: 9167257] ].

Fig. (2)
Model of bacterial mer operan determinants and expressed genes. Organic methylmercury can enter inside cell through merP, T, and E transporter while, phenylmercury transported by merG protein also both may passively diffused inside the cell. Inorganic mercury transported by merP and T to be reduced by merA(10).


5.2. mer Detoxification Genes

merA is the main gene in mer operon encodes for mercuric ion reductase enzyme, which is a flavoprotein catalyzes reduction of Hg+2 into volatile Hg0 by using NADPH located in the cytoplasm as source of electrons for the reduction of Flavin Adenine Dinucleotide (FAD) [76Liebert CA, Hall RM, Summers AO. Transposon Tn21, flagship of the floating genome. Microbiol Mol Biol Rev 1999; 63(3): 507-22.[PMID: 10477306] , 99Schottel JL. The mercuric and organomercurial detoxifying enzymes from a plasmid-bearing strain of Escherichia coli. J Biol Chem 1978; 253(12): 4341-9.[PMID: 350872] , 100Fermentation BK, Inage K, Chiba T, Metallic J, G S. Metallic in mercury-resistant pseudomonas has not and the electron described is containing group, and the enzyme for the decomposition mercuric chloride on bag, and subjected to a column (2.5 x 25 cm ) of DEAE. 1971; 36(12): 217-6.]. Hg0 is released out of the bacteria through cell membrane due to its lipid solubility without efflux system [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 22Hamlett NV, Landale EC, Davis BH, Summers AO. Roles of the Tn21 merT, merP, and merC gene products in mercury resistance and mercury binding. J Bacteriol 1992; 174(20): 6377-85.[http://dx.doi.org/10.1128/jb.174.20.6377-6385.1992] [PMID: 1328156] , 75Schelert J, Dixit V, Hoang V, Simbahan J, Drozda M, Blum P. Occurrence and characterization of mercury resistance in the hyperthermophilic archaeon Sulfolobus solfataricus by use of gene disruption. J Bacteriol 2004; 186(2): 427-37.[http://dx.doi.org/10.1128/JB.186.2.427-437.2004] [PMID: 14702312] , 76Liebert CA, Hall RM, Summers AO. Transposon Tn21, flagship of the floating genome. Microbiol Mol Biol Rev 1999; 63(3): 507-22.[PMID: 10477306] , 101Essa AMM. The effect of a continuous mercury stress on mercury reducing community of some characterized bacterial strains. Afr J Microbiol Res 2012; 6(18): 4006-12.]. The released Hg0 back to the environment causes repetition of mercury cycle. To overcome this problem, a new study used an engineered bacteria to express polyphosphate, a chelator for divalent metal, in addition to mer operon determinants to overcome metal volatilization [102Pan-Hou H. [Application of mercury-resistant genes in bioremediation of mercurials in environments]. Yakugaku Zasshi 2010; 130(9): 1143-56.[http://dx.doi.org/10.1248/yakushi.130.1143] [PMID: 20823672] ], help reducing environmental re-pollution. merA has an amino-terminal domain (NmerA) Fig. (3), which is homologous to merP and contains a pair of cysteines that directly remove Hg+2 from transport proteins cytosolic cysteines to be ready for reduction [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] ]. Mutations by insertion or deletion in merA cause Hg+2 hypersensitive strains [22Hamlett NV, Landale EC, Davis BH, Summers AO. Roles of the Tn21 merT, merP, and merC gene products in mercury resistance and mercury binding. J Bacteriol 1992; 174(20): 6377-85.[http://dx.doi.org/10.1128/jb.174.20.6377-6385.1992] [PMID: 1328156] ].

merB, codes for organomercurial lyase catalyzes demethylation of organic mercury compounds (alkyl and aryl) via cleavage of its C-Hg bond releasing a protonated organic moiety (as methane (CH4) in case of MeHg) and Hg+2 which is then reduced to Hg0 by merA using same NADPH-dependent mechanism [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 78Pepi M, Gaggi C, Bernardini E, et al. Mercury-resistant bacterial strains Pseudomonas and Psychrobacter spp. isolated from sediments of Orbetello Lagoon (Italy) and their possible use in bioremediation processes. Int Biodeterior Biodegradation 2011; 65(1): 85-91.[http://dx.doi.org/10.1016/j.ibiod.2010.09.006] , 99Schottel JL. The mercuric and organomercurial detoxifying enzymes from a plasmid-bearing strain of Escherichia coli. J Biol Chem 1978; 253(12): 4341-9.[PMID: 350872] , 103Parks JM, Guo H, Momany C, et al. Mechanism of Hg-C protonolysis in the organomercurial lyase MerB. J Am Chem Soc 2009; 131(37): 13278-85.[http://dx.doi.org/10.1021/ja9016123] [PMID: 19719173] , 104Mathema VB, Krishna B, Thakuri C, Sillanpää M, Amatya R. Study of mercury (II) chloride tolerant bacterial isolates from Baghmati River with estimation of plasmid size and growth variation for the high mercury (II) resistant Enterobacter spp. Culture 2011; 72-.].

5.3. Mechanism of Organomercurials Protonolysis by Merb

Organomercuriallyase acts as a monomer containing four cysteine residues Cys117, Cys 96, Cys 159, and Cys160. Asp99, Cys96, and Cys159 residues of the enzyme and water molecule all are involved in protonolysis reaction [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 103Parks JM, Guo H, Momany C, et al. Mechanism of Hg-C protonolysis in the organomercurial lyase MerB. J Am Chem Soc 2009; 131(37): 13278-85.[http://dx.doi.org/10.1021/ja9016123] [PMID: 19719173] ]. MeHg forms bond with Cys96, while the Cys159 site is fully reduced then the organic moiety released through two mechanisms, Fig. (4). In mechanism 1; proton from Cys159 transferred to methyl carbon and Cys159 forms covalent bond with Hg+2. In mechanism 2, Cys159 first transfer proton to Asp99 then forms a covalent bond with Hg+2 in presence of methyl group. Asp99 then transfer a proton to the methyl group and the protonated methyl moiety is released. Hg+2 is attached to the enzyme by two sulfurs of Cys96 and Cys159, and oxygen from a water molecule [103Parks JM, Guo H, Momany C, et al. Mechanism of Hg-C protonolysis in the organomercurial lyase MerB. J Am Chem Soc 2009; 131(37): 13278-85.[http://dx.doi.org/10.1021/ja9016123] [PMID: 19719173] ]. Organomercuriallyase remains attached to Hg+2 until two solvent thiols separately bind two Hg+2 and removes it [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] ].

merG helps in cellular permeability of organomercurial compounds (Phenylmercury) through effluxing [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 96Kiyono M, Pan-Hou H. The merG gene product is involved in phenylmercury resistance in Pseudomonas strain K-62. J Bacteriol 1999; 181(3): 726-30.[PMID: 9922233] , 98Das S, Dash HR, Chakraborty J. Genetic basis and importance of metal resistant genes in bacteria for bioremediation of contaminated environments with toxic metal pollutants. Appl Microbiol Biotechnol 2016; 100(7): 2967-84.[http://dx.doi.org/10.1007/s00253-016-7364-4] [PMID: 26860944] , 105Sone Y, Mochizuki Y, Koizawa K, et al. Mercurial-resistance determinants in Pseudomonas strain K-62 plasmid pMR68. AMB Express 2013; 3(1): 41.[http://dx.doi.org/10.1186/2191-0855-3-41] [PMID: 23890172] ]. Mutation by merG deletion, phenylmercury resistance was affected however, Hg+2 volatilization activity wasn’t affected. So, merG have no role in inorganic mercury compounds detoxification [96Kiyono M, Pan-Hou H. The merG gene product is involved in phenylmercury resistance in Pseudomonas strain K-62. J Bacteriol 1999; 181(3): 726-30.[PMID: 9922233] ].

Fig. (3)
Illustration for the role of NmerA in Hg+2 removal from transport proteins cytosolic cysteine to be reduced by mercuric reductase into Hg0 (11).


5.4. mer Operon Regulatory Genes

Regulatory genes are merR and merD [89Boyd ES, Barkay T. The mercury resistance operon: from an origin in a geothermal environment to an efficient detoxification machine. Front Microbiol 2012; 3: 349.[http://dx.doi.org/10.3389/fmicb.2012.00349] [PMID: 23087676] ]. merR, a regulatory gene encodes a metalloregulatory protein. It is Hg+2 dependent transcriptional repressor-activator that can sense metal concentration and control the expression of other functional mer operon genes [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 106Guo H-B, Johs A, Parks JM, et al. Structure and conformational dynamics of the metalloregulator MerR upon binding of Hg(II). J Mol Biol 2010; 398(4): 555-68.[http://dx.doi.org/10.1016/j.jmb.2010.03.020] [PMID: 20303978] , 107Park S-j, Wireman JOY, Summers A. Genetic Analysis of the Tn2l operator-promoter 1992; 174(7): 2160-71.]. It binds with the promoter-operator region (merOP) and positively and negatively regulate mer operon genes expression in presence or absence of Hg+2, respectively [8Dash HR, Das S. Bioremediation of mercury and the importance of bacterial mer genes. Int Biodeterior Biodegradation 2012; 75: 207-13.[http://dx.doi.org/10.1016/j.ibiod.2012.07.023] , 22Hamlett NV, Landale EC, Davis BH, Summers AO. Roles of the Tn21 merT, merP, and merC gene products in mercury resistance and mercury binding. J Bacteriol 1992; 174(20): 6377-85.[http://dx.doi.org/10.1128/jb.174.20.6377-6385.1992] [PMID: 1328156] , 75Schelert J, Dixit V, Hoang V, Simbahan J, Drozda M, Blum P. Occurrence and characterization of mercury resistance in the hyperthermophilic archaeon Sulfolobus solfataricus by use of gene disruption. J Bacteriol 2004; 186(2): 427-37.[http://dx.doi.org/10.1128/JB.186.2.427-437.2004] [PMID: 14702312] , 76Liebert CA, Hall RM, Summers AO. Transposon Tn21, flagship of the floating genome. Microbiol Mol Biol Rev 1999; 63(3): 507-22.[PMID: 10477306] , 87Yu Z, Li J, Li Y, et al. A mer operon confers mercury reduction in a Staphylococcus epidermidis strain isolated from Lanzhou reach of the Yellow River. Int Biodeterior Biodegradation 1981; 90: 57-63.[http://dx.doi.org/10.1016/j.ibiod.2014.02.002] , 106Guo H-B, Johs A, Parks JM, et al. Structure and conformational dynamics of the metalloregulator MerR upon binding of Hg(II). J Mol Biol 2010; 398(4): 555-68.[http://dx.doi.org/10.1016/j.jmb.2010.03.020] [PMID: 20303978] ]. Hg-free-merR (apo-merR) undergoes conformational structure changes upon Hg+2 binding and converted from repression to activation state Hg-merR [108Chang C-C, Lin L-Y, Zou X-W, Huang C-C, Chan N-L. Structural basis of the mercury(II)-mediated conformational switching of the dual-function transcriptional regulator MerR. Nucleic Acids Res 2015; 43(15): 7612-23.[http://dx.doi.org/10.1093/nar/gkv681] [PMID: 26150423] ].

merD, a gene encodes for a secondary regulatory protein, present downstream merA [109Haberstroh L, Silver S. 1984.]. MerD protein is expressed in very small amounts and downregulates the mer operon [110Lee IW, Gambill BD, Summers AO. Translation of merD in Tn21. J Bacteriol 1989; 171(4): 2222-5.[http://dx.doi.org/10.1128/jb.171.4.2222-2225.1989] [PMID: 2539363] ]. Its absence causes an increase in mer operon expression. It binds with the same operator-promoter region (merOP) as MerR [8Dash HR, Das S. Bioremediation of mercury and the importance of bacterial mer genes. Int Biodeterior Biodegradation 2012; 75: 207-13.[http://dx.doi.org/10.1016/j.ibiod.2012.07.023] , 22Hamlett NV, Landale EC, Davis BH, Summers AO. Roles of the Tn21 merT, merP, and merC gene products in mercury resistance and mercury binding. J Bacteriol 1992; 174(20): 6377-85.[http://dx.doi.org/10.1128/jb.174.20.6377-6385.1992] [PMID: 1328156] , 76Liebert CA, Hall RM, Summers AO. Transposon Tn21, flagship of the floating genome. Microbiol Mol Biol Rev 1999; 63(3): 507-22.[PMID: 10477306] ]. It acts as activation antagonist for MerR function. Invitro experimental showed that, after Hg+2 volatilization by merA, the MerR does not give up its bound Hg+2 quickly causing merA to be active. merA expression should be stopped when Hg+2 is exhausted because merA has an oxidase activity and produces toxic hydrogen peroxide in the absence of Hg+2 [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] ].

6. MER OPERON EVOLUTION, MOBILITY AND DIVERSITY

mer operon is an ancient system [97Osborn AM, Bruce KD, Strike P, Ritchie DA. Distribution, diversity and evolution of the bacterial mercury resistance (mer) operon. FEMS Microbiol Rev 1997; 19(4): 239-62.[http://dx.doi.org/10.1111/j.1574-6976.1997.tb00300.x] [PMID: 9167257] ] may be located on the chromosome [74Zeng XX, Tagn JX, Jiang P, Liu H W, Dai Z-mM, Liu X-dD. Isolation, characterization and extraction of mer gene of Hg2+ resisting strain D2. Trans Nonferrous Met Soc China 2010; 20(50621063): 507-12. [English Edition].[http://dx.doi.org/10.1016/S1003-6326(09)60170-9] ] and transferred vertically from parents to offspring or on Mobile Genetic Elements (MGE). DNA parts encode proteins that help in its mobility within bacterial genomes or between bacterial cells, facilitating Horizontal Gene Transfer (HGT) independent on reproduction [46Nascimento AM, Chartone-Souza E. Operon mer: Bacterial resistance to mercury and potential for bioremediation of contaminated environments. Genet Mol Res 2003; 2(1): 92-101.[PMID: 12917805] , 77Wireman J, Liebert CA, Smith T, et al. Association of mercury resistance with antibiotic resistance in the gram-negative fecal bacteria of primates. Association of Mercury Resistance with Antibiotic Resistance in the Gram-Negative Fecal Bacteria of Primates 1997; 63(11), 106Guo H-B, Johs A, Parks JM, et al. Structure and conformational dynamics of the metalloregulator MerR upon binding of Hg(II). J Mol Biol 2010; 398(4): 555-68.[http://dx.doi.org/10.1016/j.jmb.2010.03.020] [PMID: 20303978] , 111Wireman J, Liebert CA, Smith T, Summers AO. Association of mercury resistance with antibiotic resistance in the gram-negative fecal bacteria of primates. Appl Environ Microbiol 1997; 63(11): 4494-503.[PMID: 9361435] -114Frost LS, Leplae R, Summers AO, Toussaint A. Mobile genetic elements: the agents of open source evolution. Nat Rev Microbiol 2005; 3(9): 722-32.[http://dx.doi.org/10.1038/nrmicro1235] [PMID: 16138100] ] so, this flexibility in genome [115Dash HR, Das S. Diversity, community structure, and bioremediation potential of mercury-resistant marine bacteria of estuarine and coastal environments of Odisha, India. Environ. Sci. Pollut Res. 2015.] can help bacterial adaptation, social interactions and evolution by transferring good genes for the host as the mer genes [76Liebert CA, Hall RM, Summers AO. Transposon Tn21, flagship of the floating genome. Microbiol Mol Biol Rev 1999; 63(3): 507-22.[PMID: 10477306] , 114Frost LS, Leplae R, Summers AO, Toussaint A. Mobile genetic elements: the agents of open source evolution. Nat Rev Microbiol 2005; 3(9): 722-32.[http://dx.doi.org/10.1038/nrmicro1235] [PMID: 16138100] , 116Rankin DJ, Rocha EPC, Brown SP. What traits are carried on mobile genetic elements, and why? Heredity (Edinb) 2011; 106(1): 1-10.[http://dx.doi.org/10.1038/hdy.2010.24] [PMID: 20332804] -119Martínez JL. Antibiotics and antibiotic resistance genes in natural environments. Science 2008; 321(5887): 365-7.[http://dx.doi.org/10.1126/science.1159483] [PMID: 18635792] ]. MGE can help in the rapid spread of rare, spontaneous resistance mutants to a new bacterial population [114Frost LS, Leplae R, Summers AO, Toussaint A. Mobile genetic elements: the agents of open source evolution. Nat Rev Microbiol 2005; 3(9): 722-32.[http://dx.doi.org/10.1038/nrmicro1235] [PMID: 16138100] ]. As plasmid-borne resistance genes can be originated as point mutations in sensitive bacteria and then transferred when they are flanked by short transposons, picked up by Tn3 family transposons or as mobile cassettes by integrons [76Liebert CA, Hall RM, Summers AO. Transposon Tn21, flagship of the floating genome. Microbiol Mol Biol Rev 1999; 63(3): 507-22.[PMID: 10477306] , 114Frost LS, Leplae R, Summers AO, Toussaint A. Mobile genetic elements: the agents of open source evolution. Nat Rev Microbiol 2005; 3(9): 722-32.[http://dx.doi.org/10.1038/nrmicro1235] [PMID: 16138100] , 120Bennett PM. Genome plasticity: insertion sequence elements, transposons and integrons, and DNA rearrangement. Methods Mol Biol 2004; 266: 71-113.[PMID: 15148416] ]. mer operon as part of different types of group II transposons [121Mindlin S, Kholodii G, Gorlenko Z, et al. Mercury resistance transposons of gram-negative environmental bacteria and their classification. Res Microbiol 2001; 152(9): 811-22.[http://dx.doi.org/10.1016/S0923-2508(01)01265-7] [PMID: 11763242] , 122Bogdanova E, Minakhin L, Bass I, Volodin A, Hobman JL, Nikiforov V. Class II broad-spectrum mercury resistance transposons in Gram-positive bacteria from natural environments. Res Microbiol 2001; 152(5): 503-14.[http://dx.doi.org/10.1016/S0923-2508(01)01224-4] [PMID: 11446519] ] as Tn2, Tn501, pKLH2, pMERPH and Tn5053 in Gram-negative bacteria [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 97Osborn AM, Bruce KD, Strike P, Ritchie DA. Distribution, diversity and evolution of the bacterial mercury resistance (mer) operon. FEMS Microbiol Rev 1997; 19(4): 239-62.[http://dx.doi.org/10.1111/j.1574-6976.1997.tb00300.x] [PMID: 9167257] , 121Mindlin S, Kholodii G, Gorlenko Z, et al. Mercury resistance transposons of gram-negative environmental bacteria and their classification. Res Microbiol 2001; 152(9): 811-22.[http://dx.doi.org/10.1016/S0923-2508(01)01265-7] [PMID: 11763242] ] and Tn5085, Tn5083 [122Bogdanova E, Minakhin L, Bass I, Volodin A, Hobman JL, Nikiforov V. Class II broad-spectrum mercury resistance transposons in Gram-positive bacteria from natural environments. Res Microbiol 2001; 152(5): 503-14.[http://dx.doi.org/10.1016/S0923-2508(01)01224-4] [PMID: 11446519] , 123Matsui K, Yoshinami S, Narita M, et al. Mercury resistance transposons in Bacilli strains from different geographical regions. FEMS Microbiol Lett 2016; 363(5): fnw013.[http://dx.doi.org/10.1093/femsle/fnw013] [PMID: 26802071] ], and newly identified Tn6294 [123Matsui K, Yoshinami S, Narita M, et al. Mercury resistance transposons in Bacilli strains from different geographical regions. FEMS Microbiol Lett 2016; 363(5): fnw013.[http://dx.doi.org/10.1093/femsle/fnw013] [PMID: 26802071] ] in Gram-positive bacteria, All of them encode genes for transposition (tnpA) and resolution functions (tnpR) [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 121Mindlin S, Kholodii G, Gorlenko Z, et al. Mercury resistance transposons of gram-negative environmental bacteria and their classification. Res Microbiol 2001; 152(9): 811-22.[http://dx.doi.org/10.1016/S0923-2508(01)01265-7] [PMID: 11763242] -124Liebert CA, Hall RM, Summers AO. Transposon Tn 21. Flagship of the Floating Genome 1999; 63(3): 507-22.].

Successive exposure to mercury for a long time caused mer operon persistence and transfered between microbes through HGT and to be evolved rapidly and became more complex as merA and species evolved. Evolution happened to adapt with environment, increasing mercury toxicity due to increased industrialization [89Boyd ES, Barkay T. The mercury resistance operon: from an origin in a geothermal environment to an efficient detoxification machine. Front Microbiol 2012; 3: 349.[http://dx.doi.org/10.3389/fmicb.2012.00349] [PMID: 23087676] ] that can explain the global distribution of mer determinants and their associated mobile elements between different bacterial strains [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 97Osborn AM, Bruce KD, Strike P, Ritchie DA. Distribution, diversity and evolution of the bacterial mercury resistance (mer) operon. FEMS Microbiol Rev 1997; 19(4): 239-62.[http://dx.doi.org/10.1111/j.1574-6976.1997.tb00300.x] [PMID: 9167257] ]. So, merA was considered as a biomarker for measuring diversity in Hg detoxification and mer operon evolution [89Boyd ES, Barkay T. The mercury resistance operon: from an origin in a geothermal environment to an efficient detoxification machine. Front Microbiol 2012; 3: 349.[http://dx.doi.org/10.3389/fmicb.2012.00349] [PMID: 23087676] , 125Lal D, Lal R. Evolution of mercuric reductase (merA) gene: A case of horizontal gene transfer. Mikrobiologiia 2010; 79(4): 524-31.[PMID: 21058506] ].

A recent study on different mer operons of different Bacillus species (as tndMER3, tn6294, and others) isolated from thirteen different countries is a good example for mer diversity, mobility, evolution and horizontal distribution between different Bacillus species worldwide [123Matsui K, Yoshinami S, Narita M, et al. Mercury resistance transposons in Bacilli strains from different geographical regions. FEMS Microbiol Lett 2016; 363(5): fnw013.[http://dx.doi.org/10.1093/femsle/fnw013] [PMID: 26802071] ].

Genes that express transporter proteins merP and merT were more common to occur in earliest evolved operons which were less complex while, other alternative transporter genes as merC, merF, merE, and merH commonly occurred in more complex operons evolved recently. In organomercurial detoxification system, merG gene occurred in more recently evolved operons [89Boyd ES, Barkay T. The mercury resistance operon: from an origin in a geothermal environment to an efficient detoxification machine. Front Microbiol 2012; 3: 349.[http://dx.doi.org/10.3389/fmicb.2012.00349] [PMID: 23087676] ]. Proteins as merE, merC, merP, merD, and merT were also found to be more likely encoded on plasmids than others so, prefer to be transferred horizontally [89Boyd ES, Barkay T. The mercury resistance operon: from an origin in a geothermal environment to an efficient detoxification machine. Front Microbiol 2012; 3: 349.[http://dx.doi.org/10.3389/fmicb.2012.00349] [PMID: 23087676] ].

A recent research depended on sequencing of four different pQBR mercury resistance plasmids showed that mercury resistance transposons Tn5042 were totally similar in the four plasmids except for one base pair of merR in pQBR103 and pQBR44 differed from pQBR55 and pQBR57, indicating that Tn5042 had been transferred between different pQBR plasmids by recombination. They also found that occurrence of pQBR55, pQBR57 and pQBR103 separately in Pseudomonas fluorescens SBW25 host resulted in different response to some environmental factors as Hg(II) concentration, although similarity in their mer operon suggested the effect of other plasmid-encoded genes [8Dash HR, Das S. Bioremediation of mercury and the importance of bacterial mer genes. Int Biodeterior Biodegradation 2012; 75: 207-13.[http://dx.doi.org/10.1016/j.ibiod.2012.07.023] , 126Hall JPJ, Harrison E, Lilley AK, Paterson S, Spiers AJ, Brockhurst MA. Environmentally co-occurring mercury resistance plasmids are genetically and phenotypically diverse and confer variable context-dependent fitness effects. Environ Microbiol 2015; 17(12): 5008-22.[http://dx.doi.org/10.1111/1462-2920.12901] [PMID: 25969927] ].

Fig. (4)
Mechanisms of MerB catalysis for the Hg-C protonolysis reaction(103). Mechanism 1; Cys159 protonates the methyl group then reacts with Hg+2. Mechanism 2; hydrogen was attached to the sulfur from Cys159 transferred to Asp99 then Asp99 utilized for methyl group protonation.


6.1. Diversity of mer Operon

Several variations in structure and organization of mer operons genes are known between both Gram-negative and Gram-positive bacterial strains as in Figs. (5 and 6), for examples:

Fig. (5)
Diversity mer operons in Gram-positive bacteria. Arrows indicate the gene product translation direction.


  1. merB is more common in Gram-positive mer operons [123Matsui K, Yoshinami S, Narita M, et al. Mercury resistance transposons in Bacilli strains from different geographical regions. FEMS Microbiol Lett 2016; 363(5): fnw013.[http://dx.doi.org/10.1093/femsle/fnw013] [PMID: 26802071] , 127Huang CC, Narita M, Yamagata T, Endo G. Identification of three merB genes and characterization of a broad-spectrum mercury resistance module encoded by a class II transposon of Bacillus megaterium strain MB1. Gene 1999; 239(2): 361-6.[http://dx.doi.org/10.1016/S0378-1119(99)00388-1] [PMID: 10548738] , 128Laddaga RA, Chu L, Misra TK, Silver S. Nucleotide sequence and expression of the mercurial-resistance operon from Staphylococcus aureus plasmid pI258. Proc Natl Acad Sci USA 1987; 84(15): 5106-10.[http://dx.doi.org/10.1073/pnas.84.15.5106] [PMID: 3037534] ], while merD and merC or merF are more common in Gram-negative mer operons [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 76Liebert CA, Hall RM, Summers AO. Transposon Tn21, flagship of the floating genome. Microbiol Mol Biol Rev 1999; 63(3): 507-22.[PMID: 10477306] , 97Osborn AM, Bruce KD, Strike P, Ritchie DA. Distribution, diversity and evolution of the bacterial mercury resistance (mer) operon. FEMS Microbiol Rev 1997; 19(4): 239-62.[http://dx.doi.org/10.1111/j.1574-6976.1997.tb00300.x] [PMID: 9167257] , 129Petrovski S, Blackmore DW, Jackson KL, Stanisich VA. Mercury(II)-resistance transposons Tn502 and Tn512, from Pseudomonas clinical strains, are structurally different members of the Tn5053 family. Plasmid 2011; 65(1): 58-64.[http://dx.doi.org/10.1016/j.plasmid.2010.08.003] [PMID: 20800080] , 130Osborn AM, Bruce KD, Ritchie DA, Strike P. The mercury resistance operon of the IncJ plasmid pMERPH exhibits structural and regulatory divergence from other Gram-negative mer operons. Microbiology 1996; 142(Pt 2): 337-45.[http://dx.doi.org/10.1099/13500872-142-2-337] [PMID: 8932707] ].
  2. Narrow-spectrum mer operon genes are highly divergent compared to broad-spectrum operon genes. According to Narita, et al. in certain broad-spectrum mercury resistant Bacillus species, Polymerase Chain Reaction (PCR) product sizes of mer operon genes are identical to that of Bacillus megaterium MB1. However, in narrow-spectrum mer operon of certain Bacillus species, PCR product sizes of the targeted merP and merA regions are smaller than merP and merA of the B. megaterium MB1 [131Narita M, Chiba K, Nishizawa H, et al. Diversity of mercury resistance determinants among Bacillus strains isolated from sediment of Minamata Bay. FEMS Microbiol Lett 2003; 223(1): 73-82.[http://dx.doi.org/10.1016/S0378-1097(03)00325-2] [PMID: 12799003] ].
  3. Three different merB genes were identified in different Bacillus species [127Huang CC, Narita M, Yamagata T, Endo G. Identification of three merB genes and characterization of a broad-spectrum mercury resistance module encoded by a class II transposon of Bacillus megaterium strain MB1. Gene 1999; 239(2): 361-6.[http://dx.doi.org/10.1016/S0378-1119(99)00388-1] [PMID: 10548738] ] as in TnMER11-like transposons [123Matsui K, Yoshinami S, Narita M, et al. Mercury resistance transposons in Bacilli strains from different geographical regions. FEMS Microbiol Lett 2016; 363(5): fnw013.[http://dx.doi.org/10.1093/femsle/fnw013] [PMID: 26802071] ] resistant to different organomercurial compounds and also have multiple merR.
  4. Transcription direction of merR is same as other mer operon functional genes in Gram-positive bacteria mer operons while, merR transcription is divergent from the structural genes in the high-GC Gram-positive mer operons and Gram-negative operons except Pseudoalteromonas haloplanktis [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] , 129Petrovski S, Blackmore DW, Jackson KL, Stanisich VA. Mercury(II)-resistance transposons Tn502 and Tn512, from Pseudomonas clinical strains, are structurally different members of the Tn5053 family. Plasmid 2011; 65(1): 58-64.[http://dx.doi.org/10.1016/j.plasmid.2010.08.003] [PMID: 20800080] , 132Wang Y, Moore M, Levinson HS, Silver S, Walsh C, Mahler I. Nucleotide sequence of a chromosomal mercury resistance determinant from a Bacillus sp. with broad-spectrum mercury resistance. J Bacteriol 1989; 171(1): 83-92.[http://dx.doi.org/10.1128/jb.171.1.83-92.1989] [PMID: 2536669] , 133Griffin HG, Foster TJ, Silver S, Misra TK. Cloning and DNA sequence of the mercuric- and organomercurial-resistance determinants of plasmid pDU1358. Proc Natl Acad Sci USA 1987; 84(10): 3112-6.[http://dx.doi.org/10.1073/pnas.84.10.3112] [PMID: 3033633] ].
  5. Transposons Tn5084 and Tn5085 are identical in the genetic orientation and contain merB3, merR, merE, merT, merP and merA while, Tn5083 lacks merR2, merB2 and merB1, compared to Tn5084 and Tn5085 [122Bogdanova E, Minakhin L, Bass I, Volodin A, Hobman JL, Nikiforov V. Class II broad-spectrum mercury resistance transposons in Gram-positive bacteria from natural environments. Res Microbiol 2001; 152(5): 503-14.[http://dx.doi.org/10.1016/S0923-2508(01)01224-4] [PMID: 11446519] , 123Matsui K, Yoshinami S, Narita M, et al. Mercury resistance transposons in Bacilli strains from different geographical regions. FEMS Microbiol Lett 2016; 363(5): fnw013.[http://dx.doi.org/10.1093/femsle/fnw013] [PMID: 26802071] , 132Wang Y, Moore M, Levinson HS, Silver S, Walsh C, Mahler I. Nucleotide sequence of a chromosomal mercury resistance determinant from a Bacillus sp. with broad-spectrum mercury resistance. J Bacteriol 1989; 171(1): 83-92.[http://dx.doi.org/10.1128/jb.171.1.83-92.1989] [PMID: 2536669] ].
  6. Newly identified transposon Tn6294 has one merB. It is the first transposon to carry merA with only one N-terminal mercury binding domain, unlike all other reported broad spectrum Bacillus species that carry duplicate N-domain [123Matsui K, Yoshinami S, Narita M, et al. Mercury resistance transposons in Bacilli strains from different geographical regions. FEMS Microbiol Lett 2016; 363(5): fnw013.[http://dx.doi.org/10.1093/femsle/fnw013] [PMID: 26802071] ].
  7. TndMER3, a newly identified deleted transposon, was similar to the fragment in Bacillus species that carry merRETPA with>90% identity to Tn6294 but with no merB and transposonase genes [123Matsui K, Yoshinami S, Narita M, et al. Mercury resistance transposons in Bacilli strains from different geographical regions. FEMS Microbiol Lett 2016; 363(5): fnw013.[http://dx.doi.org/10.1093/femsle/fnw013] [PMID: 26802071] ].
  8. mer operon of Shewanella putrefaciens pMERPH does not have both merD or merR, compared to other Gram-negative bacteria suggesting that merR may be located elsewhere on the plasmid genes [130Osborn AM, Bruce KD, Ritchie DA, Strike P. The mercury resistance operon of the IncJ plasmid pMERPH exhibits structural and regulatory divergence from other Gram-negative mer operons. Microbiology 1996; 142(Pt 2): 337-45.[http://dx.doi.org/10.1099/13500872-142-2-337] [PMID: 8932707] ].
  9. Gene position differs from one operon to another as merB present between merA and merD in pDU1358 [133Griffin HG, Foster TJ, Silver S, Misra TK. Cloning and DNA sequence of the mercuric- and organomercurial-resistance determinants of plasmid pDU1358. Proc Natl Acad Sci USA 1987; 84(10): 3112-6.[http://dx.doi.org/10.1073/pnas.84.10.3112] [PMID: 3033633] ], while in broad spectrum part of Pseudomonas stutzeri pPB located between merR and merT [134Reniero D, Galli E, Barbieri P. Cloning and comparison of mercury- and organomercurial-resistance determinants from a Pseudomonas stutzeri plasmid. Gene 1995; 166(1): 77-82.[http://dx.doi.org/10.1016/0378-1119(95)00546-4] [PMID: 8529897] ].
  10. In Pseudomonas sp. Tn502 and Tn512 mer operon are related to Tn5053 with exception of merC and urf2M in newly recognized Tn502 compared to merF in Tn512 and Tn5053 [129Petrovski S, Blackmore DW, Jackson KL, Stanisich VA. Mercury(II)-resistance transposons Tn502 and Tn512, from Pseudomonas clinical strains, are structurally different members of the Tn5053 family. Plasmid 2011; 65(1): 58-64.[http://dx.doi.org/10.1016/j.plasmid.2010.08.003] [PMID: 20800080] , 135Kholodii GY, Mindlin SZ, Bass IA, Yurieva OV, Minakhina SV, Nikiforov VG. Four genes, two ends, and a res region are involved in transposition of Tn5053: A paradigm for a novel family of transposons carrying either a mer operon or an integron. Mol Microbiol 1995; 17(6): 1189-200.[http://dx.doi.org/10.1111/j.1365-2958.1995.mmi_17061189.x] [PMID: 8594337] ].

7. CO-RESISTANCE OF MERCURY AND ANTIBIOTICS

mer operons are often part of group II transposons that carry integrons with multiple antibiotic resistance genes [11Barkay T, Miller SM, Summers AO. Bacterial mercury resistance from atoms to ecosystems. FEMS Microbiol Rev 2003; 27(2-3): 355-84.[http://dx.doi.org/10.1016/S0168-6445(03)00046-9] [PMID: 12829275] ]. Antibiotics and metals resistance genes are located on the same plasmid [81Summers AO, Wireman J, Vimy MJ, et al. Mercury released from dental “silver” fillings provokes an increase in mercury- and antibiotic-resistant bacteria in oral and intestinal floras of primates. Antimicrob Agents Chemother 1993; 37(4): 825-34.[http://dx.doi.org/10.1128/AAC.37.4.825] [PMID: 8280208] , 136Christopher M, Paul O, Hamadi B. Association of metal tolerance with multidrug resistance among Environmental Bacteria from wetlands of Lake Victoria Basin 2014.]. So, mercury exposure can also promote Horizontal Gene Transfer (HGT) of both mercury and antibiotic resistance [91Jan AT, Azam M, Ali A, Haq QMR. Molecular characterization of mercury resistant bacteria inhabiting polluted water bodies of different geographical locations in India. Curr Microbiol 2012; 65(1): 14-21.[http://dx.doi.org/10.1007/s00284-012-0118-3] [PMID: 22488489] , 125Lal D, Lal R. Evolution of mercuric reductase (merA) gene: A case of horizontal gene transfer. Mikrobiologiia 2010; 79(4): 524-31.[PMID: 21058506] , 137Zeyaullah M, Islam B, Ali a. Isolation, identification and PCR amplification of merA gene from highly mercury polluted Yamuna river. Afr J Biotechnol 2010; 9(24): 3510-4., 138Pal C, Bengtsson-Palme J, Kristiansson E, Larsson DGJ. Co-occurrence of resistance genes to antibiotics, biocides and metals reveals novel insights into their co-selection potential. BMC Genomics 2015; 16: 964.[http://dx.doi.org/10.1186/s12864-015-2153-5] [PMID: 26576951] ] that explain the increasing challenge in infectious bacteria treatment due to increasing of co-resistance.

Fig. (6)
Diversity of mer operons in Gram-negative bacteria. Arrows indicate the gene product translation direction.


Six adult monkeys were examined for both mercury and antibiotics resistances of different oral and intestinal bacterial strains before and during the installation, and after the replacement of the amalgam fillings. There was an increase in MRB during the 5 weeks after installation and during the 5 weeks after replacement. MRB was also resistant to one or more antibiotics as streptomycin, kanamycin, tetracycline, ampicillin, and chloramphenicol [81Summers AO, Wireman J, Vimy MJ, et al. Mercury released from dental “silver” fillings provokes an increase in mercury- and antibiotic-resistant bacteria in oral and intestinal floras of primates. Antimicrob Agents Chemother 1993; 37(4): 825-34.[http://dx.doi.org/10.1128/AAC.37.4.825] [PMID: 8280208] ]. In a different study groups exposed to amalgam, MRB isolated from their fecal samples was found to be more resistant to antibiotics than MRB of those never exposed to amalgam [77Wireman J, Liebert CA, Smith T, et al. Association of mercury resistance with antibiotic resistance in the gram-negative fecal bacteria of primates. Association of Mercury Resistance with Antibiotic Resistance in the Gram-Negative Fecal Bacteria of Primates 1997; 63(11)], suggesting that both antibiotic and mercury resistance genes may be genetically linked [81Summers AO, Wireman J, Vimy MJ, et al. Mercury released from dental “silver” fillings provokes an increase in mercury- and antibiotic-resistant bacteria in oral and intestinal floras of primates. Antimicrob Agents Chemother 1993; 37(4): 825-34.[http://dx.doi.org/10.1128/AAC.37.4.825] [PMID: 8280208] ] and contained within the same genetic mobile element [80D SR. Prevalence of Mercury-Resistant and Antibiotic-Resistant Bacteria found in Dental Amalgam. 2014; 3(4): 1-4.] specially, the Tn21 family of transposons in which the mer locus is linked to an antibiotic multi-resistance element [77Wireman J, Liebert CA, Smith T, et al. Association of mercury resistance with antibiotic resistance in the gram-negative fecal bacteria of primates. Association of Mercury Resistance with Antibiotic Resistance in the Gram-Negative Fecal Bacteria of Primates 1997; 63(11)].

A larger scale study by Pal et al., for the co-occurrence of different metals and antibiotic resistance genes of fully sequenced 2522 bacterial genomes and 4582 plasmids as illustrated in Fig. (7), showed that although metal-antibiotic genes co-resistance was found to be rare on plasmid but, the only metal resistance genes commonly co-occurred with antibiotic-resistant genes on plasmids are mercury resistance genes as seen in Fig. (8). Moreover, about 86% of bacterial genomes contain different metals resistance genes of which 17% co-resistant with antibiotic resistance. Plasmids and genomes with different metals resistance genes were with high probability of carrying antibiotic resistant genes compared to those without metals resistance genes [138Pal C, Bengtsson-Palme J, Kristiansson E, Larsson DGJ. Co-occurrence of resistance genes to antibiotics, biocides and metals reveals novel insights into their co-selection potential. BMC Genomics 2015; 16: 964.[http://dx.doi.org/10.1186/s12864-015-2153-5] [PMID: 26576951] ].

8. MRB DETECTION METHODS

8.1. Genotypic (Molecular) Techniques

8.1.1. Polymerase Chain Reaction

Simple PCR Specific DNA sequences of the mer system determinants could be amplified from the genomic DNA of all the isolates from environmental sources using mer determinants designed primers then product can be visualized under UV on electrophoresis agarose gel as bands by staining with ethidium bromide [101Essa AMM. The effect of a continuous mercury stress on mercury reducing community of some characterized bacterial strains. Afr J Microbiol Res 2012; 6(18): 4006-12., 139Trajanovska S, Britz ML, Bhave M. Detection of heavy metal ion resistance genes in gram-positive and gram-negative bacteria isolated from a lead-contaminated site. Biodegradation 1997; 8(2): 113-24.[http://dx.doi.org/10.1023/A:1008212614677] [PMID: 9342884] -141Bruce KD, Hiorns WD, Hobman JL, Osborn AM, Strike P, Ritchie DA. Amplification of DNA from native populations of soil bacteria by using the polymerase chain reaction. Appl Environ Microbiol 1992; 58(10): 3413-6.[PMID: 1444376] ].

Real-time Reverse Transcriptase-PCR is used to detect not only the presence but also the mRNA expression of the gene [87Yu Z, Li J, Li Y, et al. A mer operon confers mercury reduction in a Staphylococcus epidermidis strain isolated from Lanzhou reach of the Yellow River. Int Biodeterior Biodegradation 1981; 90: 57-63.[http://dx.doi.org/10.1016/j.ibiod.2014.02.002] , 142Georgios M, Egki T. Phenotypic and Molecular Methods for the Detection of Antibiotic Resistance Mechanisms in Gram Negative Nosocomial Pathogens 2014.[http://dx.doi.org/10.5772/57582] ].

Fig. (7)
Overview of the resistance information from (a) 2522completely sequenced bacterial genomes and (b) 1926 plasmids harboured by those genomes from different environments. (BMRGs) biocide and metal resistance genes. (ARGs) antibiotic resistant genes [138Pal C, Bengtsson-Palme J, Kristiansson E, Larsson DGJ. Co-occurrence of resistance genes to antibiotics, biocides and metals reveals novel insights into their co-selection potential. BMC Genomics 2015; 16: 964.[http://dx.doi.org/10.1186/s12864-015-2153-5] [PMID: 26576951] ].


Fig. (8)
Co-occurrence network of resistance genes on plasmids [138Pal C, Bengtsson-Palme J, Kristiansson E, Larsson DGJ. Co-occurrence of resistance genes to antibiotics, biocides and metals reveals novel insights into their co-selection potential. BMC Genomics 2015; 16: 964.[http://dx.doi.org/10.1186/s12864-015-2153-5] [PMID: 26576951] ]. The thickness of each connection between two resistance genes is proportional to their co-occurrence times on the same plasmids. ARGs: Antibiotic Resistance Genes; MRGs: Metal ResistanceGenes; BRGs: Biocide Resistance Genes; MGEs: Mobile Genetic Elements.


8.1.2. DNA Hybridization Techniques

mer determinants encoding resistance to Hg2+ as merA or other determinants are used as labeled probes in different hybridization procedures for detecting the presence of mer determinants that are complementary to probe nucleotide sequence in mercury resistant bacteria isolated from polluted environments through positive hybridization reaction [139Trajanovska S, Britz ML, Bhave M. Detection of heavy metal ion resistance genes in gram-positive and gram-negative bacteria isolated from a lead-contaminated site. Biodegradation 1997; 8(2): 113-24.[http://dx.doi.org/10.1023/A:1008212614677] [PMID: 9342884] -141Bruce KD, Hiorns WD, Hobman JL, Osborn AM, Strike P, Ritchie DA. Amplification of DNA from native populations of soil bacteria by using the polymerase chain reaction. Appl Environ Microbiol 1992; 58(10): 3413-6.[PMID: 1444376] ]. Different hybridization techniques can be applied as Southern [139Trajanovska S, Britz ML, Bhave M. Detection of heavy metal ion resistance genes in gram-positive and gram-negative bacteria isolated from a lead-contaminated site. Biodegradation 1997; 8(2): 113-24.[http://dx.doi.org/10.1023/A:1008212614677] [PMID: 9342884] ] and Northern blot hybridization [75Schelert J, Dixit V, Hoang V, Simbahan J, Drozda M, Blum P. Occurrence and characterization of mercury resistance in the hyperthermophilic archaeon Sulfolobus solfataricus by use of gene disruption. J Bacteriol 2004; 186(2): 427-37.[http://dx.doi.org/10.1128/JB.186.2.427-437.2004] [PMID: 14702312] ], Colony blot hybridization [140Diels L, Mergeay M. DNA probe-mediated detection of resistant bacteria from soils highly polluted by heavy metals. Appl Environ Microbiol 1990; 56(5): 1485-91.[PMID: 16348196] , 143Barkay T, Fouts DL, Olson BH. Preparation of a DNA gene probe for detection of mercury resistance genes in gram-negative bacterial communities. Appl Environ Microbiol 1985; 49(3): 686-92.[PMID: 3994373] ], Fluorescent In Situ Hybridization (FISH) [144Baldi F, Gallo M, Marchetto D, Faleri C, Maida I, Fani R. Manila clams from Hg polluted sediments of Marano and Grado lagoons (Italy) harbor detoxifying Hg resistant bacteria in soft tissues. Environ Res 2013; 125: 188-96.[http://dx.doi.org/10.1016/j.envres.2012.11.008] [PMID: 23398778] ], and microarray that could be used for detection of different multiple gene at once [145Unc A, Zurek L, Peterson G, Narayanan S, Springthorpe SV, Sattar SA. Microarray assessment of virulence, antibiotic, and heavy metal resistance in an agricultural watershed creek. J Environ Qual 2012; 41(2): 534-43.[http://dx.doi.org/10.2134/jeq2011.0172] [PMID: 22370416] ] also Restriction Fragment Length Polymorphism (RFLP) could be used [139Trajanovska S, Britz ML, Bhave M. Detection of heavy metal ion resistance genes in gram-positive and gram-negative bacteria isolated from a lead-contaminated site. Biodegradation 1997; 8(2): 113-24.[http://dx.doi.org/10.1023/A:1008212614677] [PMID: 9342884] , 146Osborn AM, Bruce KD, Strike P, Ritchie DA. Polymerase Chain Reaction-Restriction Fragment Length Polymorphism Analysis Shows Divergence among mer Determinants from Gram-Negative Soil Bacteria Indistinguishable by DNA-DNA Hybridization 1993.].

8.1.3. DNA Sequencing

PCR and/or hybridization products can be sequenced to detect its homology to mer determinants [139Trajanovska S, Britz ML, Bhave M. Detection of heavy metal ion resistance genes in gram-positive and gram-negative bacteria isolated from a lead-contaminated site. Biodegradation 1997; 8(2): 113-24.[http://dx.doi.org/10.1023/A:1008212614677] [PMID: 9342884] ].

8.2. Phenotypic Techniques

8.2.1. Broth and Agar Methods (Direct Bacterial Growth)

Processed environmental samples are added into culture media as Luria-Bertani or nutrient agar (broth) supplemented with 10ppm or greater HgCl2 to detect visible growth (turbidity or colonies) in media with 10ppm HgCl2 or more. Grown bacteria are considered as MRB [104Mathema VB, Krishna B, Thakuri C, Sillanpää M, Amatya R. Study of mercury (II) chloride tolerant bacterial isolates from Baghmati River with estimation of plasmid size and growth variation for the high mercury (II) resistant Enterobacter spp. Culture 2011; 72-., 147N. Mirzazei FK, Kargar M. Isolation and identification of mercury resistant bacteria from Kor river, Iran.2008; 935-9., 148Taylor P, Figueiredo NLL, Areias A, Mendes R, Canário J, Duarte A. Mercury-Resistant Bacteria From Salt Marsh of Tagus Estuary: The Influence of Plants Presence and Mercury Contamination Levels. J Toxicol Environ Health 2014; •••: 37-41.]. Optical Density (O.D.) in different time ranges at 600 nm can be measured to detect the growth pattern of tested microorganism in presence of mercury at constant conditions [80D SR. Prevalence of Mercury-Resistant and Antibiotic-Resistant Bacteria found in Dental Amalgam. 2014; 3(4): 1-4., 149Cao D-j, Tian Z-f. Isolation and identification of a mercury resistant strain. Environ Prot Eng 2012; 38(4)].

8.2.2. Hg Utilization (Removal/Reduction) Rate

As only mercury resistant strains can utilize Hg and volatilize it, so the rate of Hg lose from the aqueous media was much higher when the cells are induced by growth in HgCl2 [150Summers AO, Lewis E. Volatilization of mercuric chloride by mercury-resistant plasmid-bearing strains of Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. J Bacteriol 1973; 113(2): 1070-2.[PMID: 4632313] ]. Tested environmental samples are inoculated in aqueous growth medium supplemented with known concentration of HgCl2 and incubated for 24 hrs at 370C. After centrifugation, the remaining concentration of mercury present in supernatant is measured using the Atomic Absorption Mercury Analyzer and compared to initial known concentration of Hg+2 to calculate its removal rate [83François F, Lombard C, Guigner JM, et al. Isolation and characterization of environmental bacteria capable of extracellular biosorption of mercury. Appl Environ Microbiol 2012; 78(4): 1097-106.[http://dx.doi.org/10.1128/AEM.06522-11] [PMID: 22156431] , 149Cao D-j, Tian Z-f. Isolation and identification of a mercury resistant strain. Environ Prot Eng 2012; 38(4)].

Moreover, about 1ml samples are taken every 4 hrs and centrifuged. Then, remaining Hg concentration is measured in supernatants after processing. Hg+2 concentrations are calculated by measuring absorbance at OD600 using standard curve. Then, the initial and the final Hg+2 concentrations can be determined and reduction rates will be calculated [87Yu Z, Li J, Li Y, et al. A mer operon confers mercury reduction in a Staphylococcus epidermidis strain isolated from Lanzhou reach of the Yellow River. Int Biodeterior Biodegradation 1981; 90: 57-63.[http://dx.doi.org/10.1016/j.ibiod.2014.02.002] ].

8.2.3. Hg0 Volatilization Assay

The ability of bacteria to volatilize mercury from added mercuric chloride is a common mercury resistance mechanism by mer genes [150Summers AO, Lewis E. Volatilization of mercuric chloride by mercury-resistant plasmid-bearing strains of Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. J Bacteriol 1973; 113(2): 1070-2.[PMID: 4632313] ]. So, volatilization can be determined by using mercury vapor analyzer [75Schelert J, Dixit V, Hoang V, Simbahan J, Drozda M, Blum P. Occurrence and characterization of mercury resistance in the hyperthermophilic archaeon Sulfolobus solfataricus by use of gene disruption. J Bacteriol 2004; 186(2): 427-37.[http://dx.doi.org/10.1128/JB.186.2.427-437.2004] [PMID: 14702312] ] or other atomic absorption spectrometry [78Pepi M, Gaggi C, Bernardini E, et al. Mercury-resistant bacterial strains Pseudomonas and Psychrobacter spp. isolated from sediments of Orbetello Lagoon (Italy) and their possible use in bioremediation processes. Int Biodeterior Biodegradation 2011; 65(1): 85-91.[http://dx.doi.org/10.1016/j.ibiod.2010.09.006] , 151Nakamura K, Nakahara H. Simplified X-ray film method for detection of bacterial volatilization of mercury chloride by Escherichia coli. Appl Environ Microbiol 1988; 54(11): 2871-3.[PMID: 3063210] ], radioactive assay or using sensitive film containing Ag+ as TEM photography film (X-ray film) which forms foggy areas due to reduction of the Ag+ emulsion of the film by the mercury vapor [148Taylor P, Figueiredo NLL, Areias A, Mendes R, Canário J, Duarte A. Mercury-Resistant Bacteria From Salt Marsh of Tagus Estuary: The Influence of Plants Presence and Mercury Contamination Levels. J Toxicol Environ Health 2014; •••: 37-41., 151Nakamura K, Nakahara H. Simplified X-ray film method for detection of bacterial volatilization of mercury chloride by Escherichia coli. Appl Environ Microbiol 1988; 54(11): 2871-3.[PMID: 3063210] ].

8.2.4. Mercuric Reductase (MR) Activity

MR activity measured depending on Hg+2 reduction mechanism by the enzyme in presence of NADPH. Hg2+ forms a complex with two cysteines of the enzyme active site. NADPH transfers a proton to FAD forming FADH-. The resulting FADH- then reduces Hg2+ into Hg0, and oxidizes back into a FAD. After reduction, the mercury is then released from the enzyme as a volatile vapor [152Lian P, Guo H-b, Riccardi D, Dong A, Parks JM, Xu Q. X-ray Structure of a Hg 2+ Complex of Mercuric Reductase (MerA) and Quantum Mechanical/Molecular Mechanical Study of Hg2+ Transfer between the C-Terminal and Buried Catalytic Site Cysteine Pairs. 2014.].

The MR activity was determined by different methods

  1. Fluorimetric measurements by oxidation of fluorescent NADPH to the non-fluorescent NADP+ due to the reduction of Hg+2 to Hg0 at specific wave lengths [144Baldi F, Gallo M, Marchetto D, Faleri C, Maida I, Fani R. Manila clams from Hg polluted sediments of Marano and Grado lagoons (Italy) harbor detoxifying Hg resistant bacteria in soft tissues. Environ Res 2013; 125: 188-96.[http://dx.doi.org/10.1016/j.envres.2012.11.008] [PMID: 23398778] ].
  2. MR assays by measuring Mercury-dependent NADPH oxidation using a UV-visible spectrophotometer [153Freedman Z, Zhu C, Barkay T. Mercury resistance and mercuric reductase activities and expression among chemotrophic thermophilic Aquificae. Appl Environ Microbiol 2012; 78(18): 6568-75.[http://dx.doi.org/10.1128/AEM.01060-12] [PMID: 22773655] , 154Sandström A, Lindskog S. Activation of mercuric reductase by the substrate NADPH. Eur J Biochem 1987; 164(1): 243-9.[http://dx.doi.org/10.1111/j.1432-1033.1987.tb11017.x] [PMID: 3104042] ] as NADPH increases the activity of MR while NADP+ has no effect on activity [154Sandström A, Lindskog S. Activation of mercuric reductase by the substrate NADPH. Eur J Biochem 1987; 164(1): 243-9.[http://dx.doi.org/10.1111/j.1432-1033.1987.tb11017.x] [PMID: 3104042] ].
  3. Determination of the remaining amount of NADPH by titration using phenazine methosulfate to produce visible formazan. The concentration of formed formazan is detected Spectrophotometric. As enzyme activity is related to the remaining amount of NADPH and the produced amount of formazan [155Ogunseitan OA. Protein method for investigating mercuric reductase gene expression in aquatic environments. Appl Environ Microbiol 1998; 64(2): 695-702.[PMID: 9464410] ].

8.2.5. Biosorption Experiments

Analysis of control and inoculated samples for metal adsorption by inductively coupled plasma optical emission spectroscopy [156Umrania VV. Bioremediation of toxic heavy metals using acidothermophilic autotrophes. Bioresour Technol 2006; 97(10): 1237-42.[http://dx.doi.org/10.1016/j.biortech.2005.04.048] [PMID: 16324838] ].

CONCLUSION

Industrialization has a great threat to the environmental mercury contamination already spread in the atmosphere, soil and water systems. Mercury causes more damage when reached to humans and animals. So, mercury usage should be restricted more to reduce its pollution. mer genes enable bacteria to convert the toxic organic or inorganic mercury forms to less toxic forms helping in mercury bioremediation as the most environmental friendly, safe and effective remediation technique.

The main mer operon genes are the merB and merA genes both can help bacteria to detoxify both organic mercurial compounds and inorganic mercury. merA, is a mercuric ion reductase enzyme, catalyzes the reduction of Hg+2 into volatile Hg0. merB, codes for organomercurial lyase catalyzes demethylation of organic mercury compounds. merT, merP, merC, merE, merF, and merH express different transporter proteins. merG helps in cellular effluxing of organomercurial compounds (Phenylmercury). merR encodes for a metalloregulatory protein, it is Hg+2 dependent transcriptional repressor-activator that can sense metal concentration and control the expression of other functional mer operon genes. Evolution and diversity in structure and organization of mer genes between different Gram-negative and Gram-positive strains affects their resistance ability as the transporter merP and merT genes were more common to occur in earliest evolved less complex operons while, other transporter genes as merC, merF, merE, merH and effluxing merG gene are commonly occurred in recently evolved, more complex operons [89Boyd ES, Barkay T. The mercury resistance operon: from an origin in a geothermal environment to an efficient detoxification machine. Front Microbiol 2012; 3: 349.[http://dx.doi.org/10.3389/fmicb.2012.00349] [PMID: 23087676] ].

Bacteria harboring the mer determinants can be genetically modified to code for resistance to other toxicants as toxic metals and be used during extreme environmental different conditions. mer determinants could be transferred into a new genetically engineered recipient suitable biological system (plant, bacteria or algae) to help in mercury remediation after removing undesired genes or adding genes to increase system harmony. Although mer system is highly understood mercury cycle in anaerobic conditions specially MeHg formation mechanism that prefers anoxic conditions is incompletely understood and requires more investigations as MeHg is the most bioaccumulative toxic form and understanding the anaerobic system will help in MeHg bioremediation.

CONFLICTS OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

CONSENT FOR PUBLICATION

Not applicable

ACKNOWLEDGEMENTS

The manuscript was drafted by Dr. Martha M. Naguib and revised and approved by Dr. Ahmed O. El-Gendy, Dr. Ahmed S. Khairalla respectively.

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(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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