51. The bottromycin epimerase BotH defines a group of atypical α/β-hydrolase-fold enzymes
- Author
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Jesko Koehnke, Sebastian Adam, Asfandyar Sikandar, Andrew W. Truman, Liliya Horbal, Laura Franz, Olga V. Kalinina, Javier Santos-Aberturas, Andriy Luzhetskyy, and HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
- Subjects
Models, Molecular ,Protein Folding ,Protein Conformation ,Racemases and Epimerases ,Peptide ,Crystallography, X-Ray ,Peptides, Cyclic ,Substrate Specificity ,Evolution, Molecular ,03 medical and health sciences ,chemistry.chemical_compound ,Protein structure ,Biosynthesis ,Bacterial Proteins ,ddc:570 ,Hydrolase ,Molecular Biology ,Gene ,030304 developmental biology ,Bottromycin ,chemistry.chemical_classification ,0303 health sciences ,Aspartic Acid ,030302 biochemistry & molecular biology ,Cell Biology ,Streptomyces ,Enzyme ,chemistry ,Biochemistry ,Multigene Family ,Protein folding - Abstract
Nature chemical biology 16(9), 1013 - 1018 (2020). doi:10.1038/s41589-020-0569-y, $\small{D}$-amino acids endow peptides with diverse, desirable properties, but the post-translational and site-specific epimerization of $\small{L}$-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 $\small{D}$-aspartate ($\small{D}$-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 $\small{L}$-Asp to $\small{D}$-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., Published by Nature Publishing Group, Basingstoke
- Published
- 2019