Enzymatic Stetter Reaction: Computational Study of the Reaction Mechanism of MenD

Quantum chemical calculations are used to investigate the detailed reaction mechanism of 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylic-acid (SEPHCHC) synthase (also known as MenD), a thiamin diphosphate-dependent decarboxylase that catalyzes formation SEPHCHC from 2-ketoglutarate and isochorismate. This enzyme is involved in menaquinone biosynthesis pathway M. tuberculosis thought potential drug target for anti-tuberculosis therapeutics. In addition, MenD shows promise biocatalyst synthesis 1,4-functionalized compounds. Models active site constructed on basis available X-ray structures, intermediates transition states optimized characterized. The calculated good agreement with prior kinetic studies gives new insights into mode action enzyme. particular, structure role tetrahedral post-decarboxylation intermediate observed structures discussed.