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Biosynthesis of the tunicamycin antibiotics proceeds via unique exo-glycal intermediates

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Author(s)

  • Filip J. Wyszynski
  • Seung Seo Lee
  • Tomoaki Yabe
  • Hua Wang
  • Juan Pablo Gomez-Escribano
  • Mervyn J. Bibb
  • Soo Jae Lee
  • Gideon J. Davies
  • Benjamin G. Davis

Department/unit(s)

Publication details

JournalNature Chemistry
DatePublished - Jul 2012
Issue number7
Volume4
Number of pages8
Pages (from-to)539-546
Original languageEnglish

Abstract

The tunicamycins are archetypal nucleoside antibiotics targeting bacterial peptidoglycan biosynthesis and eukaryotic protein N-glycosylation. Understanding the biosynthesis of their unusual carbon framework may lead to variants with improved selectivity. Here, we demonstrate in vitro recapitulation of key sugar-manipulating enzymes from this pathway. TunA is found to exhibit unusual regioselectivity in the reduction of a key alpha,beta-unsaturated ketone. The product of this reaction is shown to be the preferred substrate for TunF-an epimerase that converts the glucose derivative to a galactose. In Streptomyces strains in which another gene (tunB) is deleted, the biosynthesis is shown to stall at this exo-glycal product. These investigations confirm the combined TunA/F activity and delineate the ordering of events in the metabolic pathway. This is the first time these surprising exo-glycal intermediates have been seen in biology. They suggest that construction of the aminodialdose core of tunicamycin exploits their enol ether motif in a mode of C-C bond formation not previously observed in nature, to create an 11-carbon chain.

    Research areas

  • MANIPULATION, STREPTOMYCES, SUBSTRATE-SPECIFICITY, DERIVATIVES, HETEROLOGOUS EXPRESSION, GENE-CLUSTER, IDENTIFICATION, GLCNAC C4 EPIMERASE, DTDP-GLUCOSE 4,6-DEHYDRATASE, MASS-SPECTROMETRY

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