Antibiotic origami: selective formation of spirotetronates in abyssomicin biosynthesis

The abyssomicins are a structurally intriguing family of bioactive natural products that include compounds with potent antibacterial, antitumour and antiviral activities. The biosynthesis of the characteristic abyssomicin spirotetronate core occurs an enzyme-catalysed intramolecular Diels-Alder reac...

Full description

Saved in:

Bibliographic Details
Published in:	Chemical science (Cambridge) Vol. 15; no. 34; pp. 14009 - 14015
Main Authors:	Mbatha, Sbusisiwe Z, Back, Catherine R, Devine, Andrew J, Mulliner, Hannah M, Johns, Samuel T, Lewin, Harry, Cheung, Kaiman A, Zorn, Katja, Stach, James E M, Hayes, Martin A, van der Kamp, Marc W, Race, Paul R, Willis, Christine L
Format:	Journal Article
Language:	English
Published:	England Royal Society of Chemistry 12-08-2024 The Royal Society of Chemistry
Subjects:	Biosynthesis Chemistry Cycloaddition Diels-Alder reactions Dynamic structural analysis Enantiomers Molecular dynamics Natural products Stereoselectivity Substrates
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	The abyssomicins are a structurally intriguing family of bioactive natural products that include compounds with potent antibacterial, antitumour and antiviral activities. The biosynthesis of the characteristic abyssomicin spirotetronate core occurs an enzyme-catalysed intramolecular Diels-Alder reaction, which proceeds one of two distinct stereochemical pathways to generate products differing in configuration at the C15 spirocentre. Using the purified spirotetronate cyclases AbyU (from abyssomicin C/atrop-abyssomicin C biosynthesis) and AbmU (from abyssomicin 2/neoabyssomicin biosynthesis), in combination with synthetic substrate analogues, here we show that stereoselectivity in the spirotetronate-forming [4 + 2]-cycloaddition is controlled by a combination of factors attributable to both the enzyme and substrate. Furthermore, an achiral substrate was enzymatically cyclised to a single enantiomer of a spirocyclic product. X-ray crystal structures, molecular dynamics simulations, and assessment of substrate binding affinity and reactivity in both AbyU and AbmU establish the molecular determinants of stereochemical control in this important class of biocatalysts.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Contributed equally to this work.
ISSN:	2041-6520 2041-6539
DOI:	10.1039/d4sc03253e