CO2 reduction pathway of Methanosarcina. In this pathway, CO2 is reduced to CH4 in a stepwise manner. For each reduction step, electrons are derived from the oxidation of H2 by the energy-converting hydrogenase (Ech), the F420-reducing hydrogenase (Frh), and the methanophenazine-reducing hydrogenase (Vht), as indicated. In the final methanogenic step, the coenzyme M (CoM)-bound methyl group is reduced by coenzyme B (CoB), thereby forming CH4 and a disulfide of the two coenzymes (CoM-CoB). Reduced forms of CoM and CoB are regenerated from the disulfide by the heterodisulfide reductase (Hdr). Methanogens that lack cytochromes do not encode Ech or Vht and instead use flavin-based electron bifurcation to couple H2 oxidation to the reduction of ferredoxin (Fd) and CoM-CoB via the MvhADG:HdrABC enzyme complex (not shown). Other abbreviations: Mch, methenyl-tetrahydrosarcinapterin (methenyl-H4SPT) cyclohydrolase; Mtr, methyl-H4SPT:CoM methyltransferase; MF, methanofuran; “red” and “ox” subscripts, reduced and oxidized states of electron carriers.