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3.D.7 The H2:Heterodisulfide Oxidoreductase (HHO) Family

A single multicomponent system, the membranous H2:heterodisulfide oxidoreductase system of the methanogenic archaeon, Methanosarcina mazei Gö1 catalyzes (1) the H2-dependent reduction of 2-hydroxyphenazine by 2-hydroxyphenazine-dependent hydrogenase and (2) the dihydro-2-hydroxyphenazine-dependent reduction of the heterodisulfide of coenzyme M-SH and coenzyme B-SH (CoM-S-S-CoB) by heterodisulfide reductase. Washed inverted vesicles of M. mazei couple both processes with the transfer of H+ across the cytoplasmic membrane. The H+/2e- ratio measured was 0.9 for each reaction, and the electrochemical proton gradient generated could drive ATP synthesis via the H+-translocating ATP synthase.

M. mazei can grow on (1) H2 + CO2, (2) methanol, (3) methylamines and (4) acetate. In the pathways of methanogenesis, all substrates are converted to methyl-S-CoM (2-methylthioethane-sulfonate) either by reduction of CO2 or by demethylation of methanol, methylamine or acetate. Methane is formed from methyl-S-CoM by a two electron reduction reaction catalyzed by methyl-S-CoM reductase which uses HS-CoB (7-mercaptoheptanoylthreonine phosphate) as the electron donor. This reaction produces the heterodisulfide, CoM-S-S-CoB, which is the terminal electron acceptor of the membraneous electron transport system of M. mazei. If H2 is present, a membranous F420 [(N-L-lactyl-γ-L-glutamyl)-L-glutamic acid phosphodiester of 7,8-didemethyl-8-hydroxy-5-deazariboflavin-5&146;-phosphate]-nonreducing hydrogenase channels electrons via b-type cytochromes to the heterodisulfide reductase which reduces the terminal electron acceptor. This electron transport system, referred to as H2:heterodisulfide oxidoreductase, is coupled to proton translocation across the cytoplasmic membrane. When cells are grown on methanol, part of the methyl groups are oxidized to CO2, and reducing equivalents are transferred to coenzyme F420. In Methanosarcina strains, reduced F420 (F420H2) is reoxidized in a reaction catalyzed by the membrane-bound F420H2 dehydrogenase which is part of the F420H2:heterodisulfide oxidoreductase. Electrons are channeled to the heterodisulfide reductase, resulting in both the reduction of CoM-S-S-CoB and the formation of an electrochemical proton gradient. The resulting ΔμH+ (transmembrane electrochemical gradient of H+) is the driving force for ATP synthesis from ADP plus Pi as catalyzed by an A1A0-type ATP synthase (TC #3.2). The system is probably subject to respiratory control.

A proposed energy-coupling mechanism is presented in Figure 3 of Ide et al. (1999). Five gene products are involved where electrons are passed from H2 to the heterodimeric hydrogenase, VhoGA, then to a cytochrome b1, VhoC, then to methanophenazine (which may serve as the transmembrane proton carrier), and finally to the heterodisulfide oxidoreductase, HdrDE, which reduces CoB-S-S-CoM.

Homologues of VhoAG included numerous hydrogenases of bacteria and archaea; VhoC is distantly related to a quinone-reactive Ni2+/Fe2+-hydrogenase cytochrome b in Wolinella succinogenes; HtrD is homologous to numerous bacterial and archaeal enzymes including fumarate reductase and glycerol-3-P dehydrogenase, and HtrE, a second b-type cytochrome with five putative transmembrane spanners, has distant homologues in bacteria, other archaea and eukaryotes. In spite of the apparent mosaic origin of the components of the system, the complete system may be specific to methanogenic archaea. The H2:heterodisulfide oxidoreductase may be related to F420H2 and CO:heterodisulfide oxidoreductases which are also believed to generate a proton motive force by redox potential-driven H+ translocation.

The two reactions of the H2:heterodisulfide oxidoreductase which are coupled to H+ translocation (extrusion) are:

(1) H2 + 2-hydroxyphenazine + H+ (in) → dihydro-2-hydroxyphenazine + H+ (out)

(2) dihydro-2-hydroxyphenazine + CoM-S-S-CoB + H+ (in) →
2-hydroxyphenazine + HS-CoM + HS-CoB + H+ (out).


This family belongs to the: Iron-Sulfur Protein (ISP) Superfamily.

References associated with 3.D.7 family:

Bertran, E., W.D. Leavitt, A. Pellerin, G.M. Zane, J.D. Wall, I. Halevy, B.A. Wing, and D.T. Johnston. (2018). Deconstructing the Dissimilatory Sulfate Reduction Pathway: Isotope Fractionation of a Mutant Unable of Growth on Sulfate. Front Microbiol 9: 3110. 30619187
Brodersen, J., S. Baümer, H.J. Abken, G. Gottschalk, and U. Deppenmeier. (1999). Inhibition of membrane-bound electron transport of the methanogenic archaeon Methanosarcina mazei Gö1 by diphenyleneiodonium. Eur. J. Biochem. 259: 218-224. 9914496
Deppenmeier, U., M. Blaut, A. Mahlmann, and G. Gottschalk. (1990). Reduced coenzyme F 420H2-dependent heterosulfide oxidoreductase: a proton-translocating redox system in methanogenic bacteria. Proc. Natl. Acad. Sci USA 87: 9449-9453. 11607121
Deppenmeier, U., V. Müller, and G. Gottschalk. (1996). Pathways of energy conservation in methanogenic archaea. Arch. Microbiol. 165: 149-163. 10471795
Guiral, M., P. Tron, C. Aubert, A. Gloter, C. Iobbi-Nivol, and M.T. Giudici-Orticoni. (2005). A membrane-bound multienzyme, hydrogen-oxidizing, and sulfur-reducing complex from the hyperthermophilic bacterium Aquifex aeolicus. J. Biol. Chem. 280: 42004-42015. 16236714
Ide, T., S. Baümer, and U. Deppenmeier. (1999). Energy conservation by the H2:heterosulfide oxidoreductase from Methanosarcina mazei Gö1: identification of two proton-translocating segments. J. Bacteriol. 181: 4076-4080. 10383977
Imachi, H., M.K. Nobu, N. Nakahara, Y. Morono, M. Ogawara, Y. Takaki, Y. Takano, K. Uematsu, T. Ikuta, M. Ito, Y. Matsui, M. Miyazaki, K. Murata, Y. Saito, S. Sakai, C. Song, E. Tasumi, Y. Yamanaka, T. Yamaguchi, Y. Kamagata, H. Tamaki, and K. Takai. (2020). Isolation of an archaeon at the prokaryote-eukaryote interface. Nature 577: 519-525. 31942073
Pires, R.H., A.I. Lourenço, F. Morais, M. Teixeira, A.V. Xavier, L.M. Saraiva, and I.A. Pereira. (2003). A novel membrane-bound respiratory complex from Desulfovibrio desulfuricans ATCC 27774. Biochim. Biophys. Acta. 1605: 67-82. 12907302
Ruppert, C., S. Wimmers, T. Lemker, and V. Müller. (1998). The A1A0-ATPase from Methanosarcina mazei: cloning of the 5’ end of the aha operon encoding the membrane domain and expression of the proteolipid in a membrane-bound form in Escherichia coli. J. Bacteriol. 180: 3448-3452. 9642200
Simon, J., R.J. van Spanning, and D.J. Richardson. (2008). The organisation of proton motive and non-proton motive redox loops in prokaryotic respiratory systems. Biochim. Biophys. Acta. 1777: 1480-1490. 18930017
Stojanowic, A., G.J. Mander, E.C. Duin, and R. Hedderich. (2003). Physiological role of the F420-non-reducing hydrogenase (Mvh) from Methanothermobacter marburgensis. Arch. Microbiol. 180: 194-203. 12856108
Welte C. and Deppenmeier U. (2014). Bioenergetics and anaerobic respiratory chains of aceticlastic methanogens. Biochim Biophys Acta. 1837(7):1130-47. 24333786
Zane, G.M., H.C. Yen, and J.D. Wall. (2010). Effect of the deletion of qmoABC and the promoter-distal gene encoding a hypothetical protein on sulfate reduction in Desulfovibrio vulgaris Hildenborough. Appl. Environ. Microbiol. 76: 5500-5509. 20581180
Zbell, A.L. and R.J. Maier. (2009). Role of the Hya hydrogenase in recycling of anaerobically produced H2 in Salmonella enterica serovar Typhimurium. Appl. Environ. Microbiol. 75: 1456-1459. 19114523