α-Keto Acid Chain Elongation Reactions Involved in the Biosynthesis of Coenzyme B (7-Mercaptoheptanoyl Threonine Phosphate) in Methanogenic Archaea

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Abstract
The biochemistry of the 13 steps involved in the conversion of α-ketoglutarate and acetylCoA to α-ketosuberate, a precursor to the coenzymes coenzyme B (7-mercapto heptanoylthreonine phosphate) and biotin, has been established in Methanosarcina thermophila. These series of reactions begin with the condensation of α-ketoglutarate and acetylCoA to form trans-homoaconitate. The trans-homoaconitate is then hydrated and dehydrated to cis-homoaconitate with (S)-homocitrate serving as an intermediate. Rehydration of the cis-homoaconitate produces (−)-threo-isohomocitrate [(2R,3S)-1-hydroxy-1,2,4-butanetricarboxylic acid], which undergoes a NADP+-dependent oxidative decarboxylation to produce α-ketoadipate. The resulting α-ketoadipate then undergoes two consecutive sets of α-ketoacid chain elongation reactions to produce α-ketosuberate. In each of these sets of reactions, it has been shown that the homologues of cis-homoaconitate, homocitrate, and (−)-threo-isohomocitrate serve as intermediates. The protein product of the Methanococcus jannaschii MJ0503 gene aksA (AksA) was found to catalyze the condensation of α-ketoglutarate and acetylCoA to form trans-homoaconitate. This gene product also catalyzed the condensation of α-ketoadipate or α-ketopimelate with acetylCoA to form, respectively, the (R)-homocitrate homologues of (R)-2-hydroxy-1,2,5-pentanetricarboxylic acid and (R)-2-hydroxy-1,2,6-hexanetricarboxylic acid. The α-ketosuberate resulting from this series of reactions then undergoes a nonoxidative decarboxylation to form 7-oxoheptanoic acid, a precursor to coenzyme B, and an oxidative decarboxylation to form pimelate, the precursor to biotin. Of the 13 intermediates in this pathway, eight have not previously been reported as occurring in biological systems.