Methanogens which solely utilize the hydrogenotrophic pathway have electron transport systems that are different from the electron transport systems of generalist methanogen species like Methanosarcina acetivorans. The generalist organism M. acetivorans is capable of using the methylotrophic, carboxidotrophic, and the acetoclastic pathways, but Methyl hesperidin cannot use the hydrogenotrophic or methyl respiration pathways due to the lack of expression of suitable hydrogenases. We wanted to identify proteins that form complexes with coenzyme M-coenzyme B heterodisulfide reductase in M. acetivorans. HdrED is essential for methylotrophic and aceticlastic growth and is likely to participate in protein:protein interactions with other enzymes of the methanogenesis pathway in Methanosarcina. Previous reports showed that CO oxidation can be coupled to CoM-S-S-CoB reduction in cell extracts in Methanosarcina barkeri MS. We propose that the Hdr:ACDS:Mer complex is a multienzyme ����router���� that directs substrates and electrons through either the acetyl-CoA or methanogenesis pathways by connecting the CoMS-S-CoB, acetyl-CoA, and CH3-H4MPT metabolic nodes. Despite the importance of several multienzyme complexes in biology it is unusual that acetyl-CoA, a major node involved in carbon fixation, is physically linked with the electron transport system in Methanosarcina by the Hdr:ACDS:Mer multienzyme complex. Physical linkage of ACDS and Mer in M. acetivorans has intriguing implications as to how carbon flux through the oxidative branch of methanogenesis and Hypaconitine biosynthesis pathways in this organism is controlled. ACDS and Mer both use CH3-H4MPT as substrate, and physically linking these two enzymes means their active sites are in direct competition for substrate. Therefore, as CH3-H4MPT is produced by Mtr, whether or not it is funneled through the oxidative branch of the methylotrophic methanogenesis pathway is dependent on the rate at which it enters the Mer active site. If Mer is not in a favorable conformation to accept substrate, methyl-H4MPT will be available for ACDS to convert into acetyl-CoA for biosynthesis.