Siderophore Synthetase DesD Catalyzes N-to-C Condensation in Desferrioxamine Biosynthesis

Jinping Yang, Victoria S. Banas, Gerry S.M. Rivera, Timothy A. Wencewicz

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Desferrioxamine siderophores are assembled by the nonribosomal-peptide-synthetase-independent siderophore (NIS) synthetase enzyme DesD via ATP-dependent iterative condensation of three N1-hydroxy-N1-succinyl-cadaverine (HSC) units. Current knowledge of NIS enzymology and the desferrioxamine biosynthetic pathway does not account for the existence of most known members of this natural product family, which differ in substitution patterns of the N- and C-termini. The directionality of desferrioxamine biosynthetic assembly, N-to-C versus C-to-N, is a longstanding knowledge gap that is limiting further progress in understanding the origins of natural products in this structural family. Here, we establish the directionality of desferrioxamine biosynthesis using a chemoenzymatic approach with stable isotope incorporation and dimeric substrates. We propose a mechanism where DesD catalyzes the N-to-C condensation of HSC units to establish a unifying biosynthetic paradigm for desferrioxamine natural products in Streptomyces.

Original languageEnglish
JournalACS Chemical Biology
DOIs
StateAccepted/In press - 2023

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