Hijacking a hydroxyethyl unit from a central metabolic ketose into a nonribosomal peptide assembly line.

Proceedings of the National Academy of Sciences of the United States of America
Chao PengGong-Li Tang

Abstract

Nonribosomal peptide synthetases (NRPSs) usually catalyze the biosynthesis of peptide natural products by sequential selection, activation, and condensation of amino acid precursors. It was reported that some fatty acids, α-ketoacids, and α-hydroxyacids originating from amino acid metabolism as well as polyketide-derived units can also be used by NRPS assembly lines as an alternative to amino acids. Ecteinascidin 743 (ET-743), naphthyridinomycin (NDM), and quinocarcin (QNC) are three important antitumor natural products belonging to the tetrahydroisoquinoline family. Although ET-743 has been approved as an anticancer drug, the origin of an identical two-carbon (C(2)) fragment among these three antibiotics has not been elucidated despite much effort in the biosynthetic research in the past 30 y. Here we report that two unexpected two-component transketolases (TKases), NapB/NapD in the NDM biosynthetic pathway and QncN/QncL in QNC biosynthesis, catalyze the transfer of a glycolaldehyde unit from ketose to the lipoyl group to yield the glycolicacyl lipoic acid intermediate and then transfer the C(2) unit to an acyl carrier protein (ACP) to form glycolicacyl-S-ACP as an extender unit for NRPS. Our results demonstrate a unique NRPS ...Continue Reading

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Citations

Aug 6, 2013·Chemistry & Biology·Yi-Ling DuKatherine S Ryan
Mar 26, 2013·Current Opinion in Chemical Biology·Michael MüllerMartina Pohl
Oct 25, 2016·Nature Chemical Biology·Jinru ZhangJiahai Zhou
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Jan 19, 2017·Angewandte Chemie·Chengzhang FuRolf Müller
Oct 18, 2018·Proceedings of the National Academy of Sciences of the United States of America·Yue ZhangGong-Li Tang
Sep 17, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xiaojing HuQianjin Kang
Jun 16, 2018·Nature Communications·Feifei QiShengying Li

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