S2: Design and generation of a transaminase for sitagliptin manufacture

A greener, biocatalytic process for the manufacture of sitagliptin has been developed by Codexis and Merck in collaboration.  Sitagliptin is the active ingredient in Januvia®, a pharmaceutic for type II diabetes in high and growing demand worldwide.  The current manufacturing process for this chiral amine involves a rhodium-catalyzed asymmetric hydrogenation of a ketone-derived unprotected enamine.  In biology, natural ketones are converted directly to chiral amines by transaminases.  However, no available transaminase exhibited any detectable activity on the pro-sitagliptin ketone.  Using in silico design, Codex engineered a transaminase to obtain marginal initial activity on the substrate.  Directed evolution ultimately provided a biocatalyst whose performance, improved by several orders of magnitude, enabled a practical manufacturing process.  In addition, the lineage of evolved transaminases has broad applicability for the synthesis of R-amines that previously were only accessible by resolution.