A Long-Range Acting Dehydratase Domain as the Missing Link for C17-Dehydration in Iso-Migrastatin Biosynthesis.

Abstract

The dehydratase domains (DHs) of the iso-migrastatin (iso-MGS) polyketide synthase (PKS) were investigated by systematic inactivation of the DHs in module-6, -9, -10 of MgsF (i.e., DH6, DH9, DH10) and module-11 of MgsG (i.e., DH11) in vivo, followed by structural characterization of the metabolites accumulated by the mutants, and biochemical characterization of DH10 in vitro, using polyketide substrate mimics with varying chain lengths. These studies allowed us to assign the functions for all four DHs, identifying DH10 as the dedicated dehydratase that catalyzes the dehydration of the C17 hydroxy group during iso-MGS biosynthesis. In contrast to canonical DHs that catalyze dehydration of the β-hydroxy groups of the nascent polyketide intermediates, DH10 acts in a long-range manner that is unprecedented for type I PKSs, a novel dehydration mechanism that could be exploited for polyketide structural diversity by combinatorial biosynthesis and synthetic biology.

• Authors: Bo Zhang, Zhengren Xu, Qihui Teng, Guohui Pan, Ming Ma, Ben Shen
• Journal: Angewandte Chemie (International ed. in English) (Angew Chem Int Ed Engl) Vol. 56 Issue 25 Pg. 7247-7251 (06 12 2017) ISSN: 1521-3773 [Electronic] Germany
• PMID: 28464455 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Macrolides
• Piperidones
• isomigrastatin
• Water
• Polyketide Synthases
• Hydro-Lyases

Topics

• Catalysis
• Hydro-Lyases (metabolism)
• Macrolides (chemistry, metabolism)
• Piperidones (chemistry, metabolism)
• Polyketide Synthases (chemistry, metabolism)
• Protein Conformation
• Protein Domains
• Substrate Specificity
• Water (chemistry)