The bottromycin epimerase BotH defines a group of atypical α/β-hydrolase-fold enzymes

Sikandar, A., Franz, L., Adam, S., Santos-Aberturas, J., Horbal, L., Luzhetskyy, A., Truman, A. W., Kalinina, O. V. and Koehnke, J. (2020) The bottromycin epimerase BotH defines a group of atypical α/β-hydrolase-fold enzymes. Nature Chemical Biology, 16(9), pp. 1013-1018. (doi: 10.1038/s41589-020-0569-y) (PMID:32601484)

Abstract

D-amino acids endow peptides with diverse, desirable properties, but the post-translational and site-specific epimerization of L-amino acids into their D-counterparts is rare and chemically challenging. Bottromycins are ribosomally synthesized and post-translationally modified peptides that have overcome this challenge and feature a D-aspartate (D-Asp), which was proposed to arise spontaneously during biosynthesis. We have identified the highly unusual α/β-hydrolase (ABH) fold enzyme BotH as a peptide epimerase responsible for the post-translational epimerization of L-Asp to D-Asp during bottromycin biosynthesis. The biochemical characterization of BotH combined with the structures of BotH and the BotH–substrate complex allowed us to propose a mechanism for this reaction. Bioinformatic analyses of BotH homologs show that similar ABH enzymes are found in diverse biosynthetic gene clusters. This places BotH as the founding member of a group of atypical ABH enzymes that may be able to epimerize non-Asp stereocenters across different families of secondary metabolites.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Koehnke, Professor Jesko
• Authors: Sikandar, A., Franz, L., Adam, S., Santos-Aberturas, J., Horbal, L., Luzhetskyy, A., Truman, A. W., Kalinina, O. V., and Koehnke, J.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Nature Chemical Biology
• Publisher: Nature Research
• ISSN: 1552-4450
• ISSN (Online): 1552-4469
• Published Online: 29 June 2020
• Copyright Holders: Copyright © 2020 Springer Nature
• First Published: First published in Nature Chemical Biology 16(9):1013-1018
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher