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Coupling of Ferredoxin and Heterodisulfide Reduction Via Coupling of ferredoxin and heterodisulfide reduction via electron bifurcation in hydrogenotrophic methanogenic archaea Anne-Kristin Kaster, Johanna Moll, Kristian Parey, and Rudolf K. Thauer1 Max Planck Institute for Terrestrial Microbiology, 35043 Marburg, Germany Edited* by Ralph S. Wolfe, University of Illinois, Urbana, IL, and approved December 27, 2010 (received for review November 9, 2010) In methanogenic archaea growing on H2 and CO2 the first step in the polyferredoxin is not known but can be predicted to lie be- + methanogenesis is the ferredoxin-dependent endergonic reduc- tween that of the 2 H /H2 couple (−414 mV) and that of the tion of CO2 with H2 to formylmethanofuran and the last step is CO2 + MFR/formyl-MFR couple (−520 mV) (4, 5). The enzyme the exergonic reduction of the heterodisulfide CoM-S-S-CoB with system catalyzing reaction 3a has not yet been identified. Hydro- H2 to coenzyme M (CoM-SH) and coenzyme B (CoB-SH). We re- genotrophic methanogens do contain at least one membrane-as- cently proposed that in hydrogenotrophic methanogens the two sociated energy-converting [NiFe]-hydrogenase catalyzing the H+ reactions are energetically coupled via the cytoplasmic MvhADG/ or Na+ motive force-driven reduction of Fd with H . However, HdrABC complex. It is reported here that the purified complex 2 these enzymes appear to have a mainly anabolic function (6–9): from Methanothermobacter marburgensis catalyzes the CoM-S-S- CoB-dependent reduction of ferredoxin with H2. Per mole CoM-S- þ → 2À þ þ [3a] S-CoB added, 1 mol of ferredoxin (Fd) was reduced, indicating H2 Fdox Fdred 2H an electron bifurcation coupling mechanism: 2H2 + Fdox + CoM-S- 2À + À þ S-CoB→Fdred + CoM-SH + CoB-SH + 2H : This stoichiometry of cou- 2 Fdred þ 2H þ CO2 þ MFR → Fdox þ formyl-MFR þ H2O: pling is consistent with an ATP gain per mole methane from 4 H2 [3b] and CO2 of near 0.5 deduced from an H2-threshold concentration of MICROBIOLOGY 8 Pa and a growth yield of up to 3 g/mol methane. Reaction 2 has been proposed to be catalyzed by the cytoplasmic flavin-based electron bifurcation | metronidazole | Methanosarcina MvhADG/HdrABC complex composed of the [NiFe]-hydroge- fi barkeri | hydrogenase | heterodisulfide reductase nase MvhADG and the heterodisul de reductase HdrABC, which is an iron–sulfur flavoprotein (Fig. S1). The two enzymes are electrically connected via the [2Fe2S] protein MvhD (9, 10). ethanogenesis from H and CO is an important reaction 2 2 The problem was that the purified complex catalyzed reaction 2 Min the global methane cycle (1). It is mediated by hydro- fi genotrophic methanogenic archaea (2). These archaea appear to at signi cant rates only in the presence of viologen dyes that mainly involve only two membrane-associated enzymes in their were reduced with H2 and reoxidized with CoM-S-S-CoB during catalysis (11). energy metabolism, a methyltransferase (MtrA-H) and an A1Ao- ATP synthase (AhaA-IK). The methyltransferase reaction is Over 20 y ago Bobik and Wolfe found that cell extracts of associated with the buildup of an electrochemical sodium ion Methanothermobacter thermautotrophicus (a hydrogenotrophic potential, which is used via the ATP synthase to drive the syn- methanogen) catalyze the reduction of CO2 to formyl-MFR with thesis of ATP (3). All of the other enzymes required for CO2 H2 (12) and the reduction of metronidazole (MTZ) with H2 (13) reduction with H2 to methane are found in the cytoplasmic cell only in the presence of CoM-S-S-CoB. MTZ reduction (14, 15) fraction. The cytoplasmic enzymes include the enzymes catalyz- and CO2 reduction to formyl-MFR (16, 17) are now known to be ing the first step and the last step in methanogenesis, namely the Fd-dependent reactions. With this knowledge the findings by endergonic reduction of CO2 and methanofuran (MFR) with H2 Bobik and Wolfe (12, 13) can be interpreted to indicate that in cell to formyl-MFR (reaction 1) and the exergonic reduction of the extracts of M. thermautotrophicus the reduction of Fd with H2 and fi heterodisul de CoM-S-S-CoB with H2 to coenzyme M (CoM- the reduction of CoM-S-S-CoB (Eo′ = −140 mV) with H2 are SH) and coenzyme B (CoB-SH) (reaction 2): coupled via the recently discovered mechanism of flavin-based electron bifurcation (18–21). Via this novel mechanism exergonic o′ H2 þ CO2 þ MFR → formyl-MFR þ H2O ΔG ¼þ20 kJ=mol and endergonic redox reactions with acceptor/donor potentials [1] between 0 and −500 mV can be coupled without involving membrane proteins. We therefore proposed in 2008 (2) that the ′ MvhADG/HdrABC complex couples the endergonic reaction 3a H þ CoM-S-S-CoB → CoM-SH þ CoB-SH ΔGo 2 to the exergonic reaction 2. The experimental evidence is now ¼ − 55 kJ=mol: [2] presented for the complex purified from the hydrogenotrophic methanogen Methanothermobacter marburgensis. The free energy change ΔG associated with reaction 1 is more positive and that associated with reaction 2 is less negative at physiological concentrations of substrates and products (2). The Author contributions: A.-K.K. and R.K.T. designed research; A.-K.K. and K.P. performed remaining question is, How are the two cytoplasmic reactions research; J.M. contributed new reagents/analytic tools; A.-K.K. and R.K.T analyzed data; coupled energetically? and A.-K.K. and R.K.T. wrote the paper. The reduction of CO2 with H2 to formyl-MFR (reaction 1)is The authors declare no conflict of interest. composed of the two partial reactions 3a and 3b that are de- *This Direct Submission article had a prearranged editor. pendent on ferredoxin (Fd) as electron carrier. Reaction 3b is 1To whom correspondence should be addressed. E-mail: [email protected]. catalyzed by a cytoplasmic formyl-MFR dehydrogenase that uses This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. a polyferredoxin as electron carrier. The redox potential (Eo′)of 1073/pnas.1016761108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1016761108 PNAS Early Edition | 1of6 Downloaded by guest on September 26, 2021 Results In MvhADG/HdrABC activity assays Fd with two [4Fe4S] clusters from Clostridium pasteurianum (Eo′ = −400 mV; n =2)(22)and − − an absorption maximum at 390 nm (ε = 30,000 M 1·cm 1) (23) was used rather than one of the several ferredoxins from M. marburgensis (9), trusting the experience that even ferredoxins from very distantly related organisms are functionally inter- changeable (24). The reduction of Fd was followed by measuring − − the decrease in absorbance at 390 nm (Δε = 11,000 M 1·cm 1) (25). Where indicated, MTZ was used as an artificial electron acceptor, its reduction being followed by measuring the decrease − − in absorbance at 320 nm (ε = Δε = 9,300 M 1·cm 1) (13, 26). MTZ is rapidly reduced by reduced Fd and Fd-like proteins in a four- Fig. 1. CoM-S-S-CoB dependence of (A) ferredoxin (Fd) reduction and of (B) electron consuming spontaneous reaction (n = 4) that proceeds metronidazole (MTZ) reduction with H2 catalyzed by a cell extract of M. irreversibly (27). marburgensis. The assays were performed at 60 °C in 1.5-mL anaerobic The heterodisulfide used in the assays was a 2:1:1 mixture of cuvettetes containing 0.75 mL assay mixture and 100% H2 as the gas phase. CoM-S-S-CoB, CoM-S-S-CoM, and CoB-S-S-CoB (Fig. S2). The The 0.75-mL assay mixture contained 1.6 M potassium phosphate (pH 7), 1 ∼ μ ∼ μ μ mixture rather than pure CoM-S-S-CoB was used because of the mM CoM-S-S-CoB, 30 g(A)or 140 g(B) cell extract, and either 35 MFd (A) or 150 μM MTZ (B). The reduction was started by CoM-S-S-CoB and fol- property of CoM-S-S-CoB to spontaneously react to CoM-S-S- lowed photometrically at 390 nm (A) or 320 nm (B). After 30 s both Fd and CoM and CoB-S-S-CoB until equilibrium is reached even under MTZ were reduced to 100%. acidic conditions during freezing (concentrating) as a prerequisite for lyophilization. Interestingly, the disproportionation of CoM- S-S-CoB appears also to take place in vivo as evidenced by the minute) before and 4 units/mg after incubation of the cell extract at + finding that Methanothermobacter species contain a NADP - 4°Cwith100%H2. dependent CoM-S-S-CoM reductase (28). We convinced our- When in the reduction assays cuvettetes and rubber stoppers selves with pure CoM-S-S-CoM and CoB-S-S-CoB that under the were used that had previously been in contact with methyl viol- assay conditions the two homodisulfides did not serve as sub- ogen or benzyl viologen (BV), the cell extracts catalyzed the strates for the MvhADG/HdrABC complex when present alone. reduction of Fd or of MTZ with H2 already in the absence of When present together, because of their synproportionation to CoM-S-S-CoB. At BV concentrations of ∼25 μM the reaction CoM-S-S-CoB, some activity was observed that was, however, became essentially independent of CoM-S-S-CoB as shown for negligible (<2 nmol/min in the 0.75-mL assay) at low concen- MTZ reduction in Fig. S3. An interpretation of this result is that trations of the two homodisulfides (<1 mM). In the experiments it the MvhADG/HdrABC complex catalyzes the reduction of was additionally ascertained that CoM-SH and CoB-SH (alone or viologen dyes with H2 in the absence of CoM-S-S-CoB (11) and together) could not substitute for CoM-S-S-CoB.
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