PMID- 32601484
OWN - NLM
STAT- MEDLINE
DCOM- 20201113
LR  - 20220716
IS  - 1552-4469 (Electronic)
IS  - 1552-4450 (Linking)
VI  - 16
IP  - 9
DP  - 2020 Sep
TI  - The bottromycin epimerase BotH defines a group of atypical alpha/beta-hydrolase-fold 
      enzymes.
PG  - 1013-1018
LID - 10.1038/s41589-020-0569-y [doi]
AB  - 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 
      alpha/beta-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.
FAU - Sikandar, Asfandyar
AU  - Sikandar A
AD  - Workgroup Structural Biology of Biosynthetic Enzymes, Helmholtz Institute for 
      Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research 
      (HZI), Saarland University, Saarbrucken, Germany.
FAU - Franz, Laura
AU  - Franz L
AUID- ORCID: 0000-0003-1649-3375
AD  - Workgroup Structural Biology of Biosynthetic Enzymes, Helmholtz Institute for 
      Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research 
      (HZI), Saarland University, Saarbrucken, Germany.
FAU - Adam, Sebastian
AU  - Adam S
AD  - Workgroup Structural Biology of Biosynthetic Enzymes, Helmholtz Institute for 
      Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research 
      (HZI), Saarland University, Saarbrucken, Germany.
FAU - Santos-Aberturas, Javier
AU  - Santos-Aberturas J
AUID- ORCID: 0000-0002-6689-8111
AD  - Department of Molecular Microbiology, John Innes Centre, Norwich, UK.
FAU - Horbal, Liliya
AU  - Horbal L
AD  - Department of Microbial Natural Products, Actinobacteria Metabolic Engineering 
      Group, HIPS, HZI, Saarland University, Saarbrucken, Germany.
FAU - Luzhetskyy, Andriy
AU  - Luzhetskyy A
AD  - Department of Microbial Natural Products, Actinobacteria Metabolic Engineering 
      Group, HIPS, HZI, Saarland University, Saarbrucken, Germany.
FAU - Truman, Andrew W
AU  - Truman AW
AUID- ORCID: 0000-0001-5453-7485
AD  - Department of Molecular Microbiology, John Innes Centre, Norwich, UK.
FAU - Kalinina, Olga V
AU  - Kalinina OV
AD  - Drug Bioinformatics Group, HIPS, HZI, Saarland University, Saarbrucken, Germany.
AD  - Medical Faculty, Saarland University, Homburg, Germany.
FAU - Koehnke, Jesko
AU  - Koehnke J
AUID- ORCID: 0000-0002-7153-1365
AD  - Workgroup Structural Biology of Biosynthetic Enzymes, Helmholtz Institute for 
      Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research 
      (HZI), Saarland University, Saarbrucken, Germany. jesko.koehnke@glasgow.ac.uk.
AD  - School of Chemistry, University of Glasgow, Glasgow, UK. 
      jesko.koehnke@glasgow.ac.uk.
LA  - eng
GR  - BBS/E/J/000PR9790/BB_/Biotechnology and Biological Sciences Research 
      Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200629
PL  - United States
TA  - Nat Chem Biol
JT  - Nature chemical biology
JID - 101231976
RN  - 0 (Bacterial Proteins)
RN  - 0 (Peptides, Cyclic)
RN  - 1393-68-6 (bottromycin)
RN  - 30KYC7MIAI (Aspartic Acid)
RN  - EC 5.1.- (Racemases and Epimerases)
SB  - IM
EIN - Nat Chem Biol. 2020 Jul 15;:. PMID: 32669684
MH  - Aspartic Acid/chemistry/metabolism
MH  - Bacterial Proteins/chemistry/genetics/metabolism
MH  - Crystallography, X-Ray
MH  - Evolution, Molecular
MH  - Models, Molecular
MH  - Multigene Family
MH  - Peptides, Cyclic/metabolism
MH  - Protein Conformation
MH  - Protein Folding
MH  - Racemases and Epimerases/*chemistry/genetics/*metabolism
MH  - Streptomyces/enzymology/genetics
MH  - Substrate Specificity
EDAT- 2020/07/01 06:00
MHDA- 2020/11/18 06:00
CRDT- 2020/07/01 06:00
PHST- 2019/12/05 00:00 [received]
PHST- 2020/05/13 00:00 [accepted]
PHST- 2020/07/01 06:00 [pubmed]
PHST- 2020/11/18 06:00 [medline]
PHST- 2020/07/01 06:00 [entrez]
AID - 10.1038/s41589-020-0569-y [pii]
AID - 10.1038/s41589-020-0569-y [doi]
PST - ppublish
SO  - Nat Chem Biol. 2020 Sep;16(9):1013-1018. doi: 10.1038/s41589-020-0569-y. Epub 
      2020 Jun 29.