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B6db references: 25730866

type Journal Article
authors Du YL, Alkhalaf LM, Ryan KS
title In vitro reconstitution of indolmycin biosynthesis reveals the molecular basis of oxazolinone assembly
journal Proc Natl Acad Sci U S A
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ui 25730866
year (2015)
volume 112
number 9
pages 2717-22
keywords antibiotic; biosynthesis; indolmycin
abstract The bacterial tryptophanyl-tRNA synthetase inhibitor indolmycin features a unique oxazolinone heterocycle whose biogenetic origins have remained obscure for over 50 years. Here we identify and characterize the indolmycin biosynthetic pathway, using systematic in vivo gene inactivation, in vitro biochemical assays, and total enzymatic synthesis. Our work reveals that a phenylacetate-CoA ligase-like enzyme Ind3 catalyzes an unusual ATP-dependent condensation of indolmycenic acid and dehydroarginine, driving oxazolinone ring assembly. We find that Ind6, which also has chaperone-like properties, acts as a gatekeeper to direct the outcome of this reaction. With Ind6 present, the normal pathway ensues. Without Ind6, the pathway derails to an unusual shunt product. Our work reveals the complete pathway for indolmycin formation and sets the stage for using genetic and chemoenzymatic methods to generate indolmycin derivatives as potential therapeutic agents.
last changed 2018/02/27 13:28

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