Bacterial MenDs for the synthesis of non-physiological compounds

LAURA S. MAZZAFERRO; ALEXANDRA WALTER; ALEXANDER FRIES; JODIE JOHNSTON ; LAURA NIGON; MICHAEL MÜLLER

Simposio; Unique cofactor-dependent enzymes in microbes; 2017

In the first committed step towards the biosynthesis of menaquinone in bacteria, the thiamine-dependent enzyme SEPHCHC-synthase (MenD) catalyzes the 1,4-addition from α-ketoglutarate to isochorismate. In this work, a docking model of MenD from E. coli (EcMenD) and the recently available 3D structure of MenD from Mycobacterium tuberculosis (MtbMenD) were compared in relation to the binding of isochorismate. Although the EcMenD and MtbMenD share low identity at the amino acid level (ca. 30%), some of the residues that interact with isochorismate are conserved and positioned in a similar manner. In view of these similarities, the substrate scope of MenD from the different sources was evaluated. The enzymes were shown to catalyze the 1,4-addition of α-ketoglutarate to cyclic compounds that resemble the structure of the physiological substrate. The inherent promiscuity of MenD can be therefore exploited for the synthesis of highly functionalized, non-physiological, compounds.