Biosynthesis of Octacosamicin A: Uncommon Starter/extender Units and Product Releasing via Intermolecular Amidation

  • Chembiochem. 2024 Jan 2;25(1):e202300590. doi: 10.1002/cbic.202300590.
Yanghui Liao  1 ,  Xue-Jiao Wang  1 ,  Guang-Lei Ma  2 ,  Hartono Candra  1 ,  Sean Lee Qiu En  1 ,  Srashti Khandelwal  1 ,  Zhao-Xun Liang  1
Affiliations
  • 1. School of Biological Sciences, Nanyang Technological University, Singapore, 67551, Singapore.
  • 2. Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, 314102, China.
PMID: 37908177 DOI: 10.1002/cbic.202300590
Abstract

Octacosamicin A is an Antifungal metabolite featuring a linear polyene-polyol chain flanked by N-hydroxyguanidine and glycine moieties. We report here that sub-inhibitory concentrations of streptomycin elicited the production of octacosamicin A in Amycolatopsis azurea DSM 43854T . We identified the biosynthetic gene cluster (oca BGC) that encodes a modular polyketide synthase (PKS) system for assembling the polyene-polyol chain of octacosamicin A. Our analysis suggested that the N-hydroxyguanidine unit originates from a 4-guanidinobutyryl-CoA starter unit, while the PKS incorporates an α-hydroxyketone moiety using a (2R)-hydroxymalonyl-CoA extender unit. The modular PKS system contains a non-canonical terminal module that lacks thioesterase (TE) and acyl carrier protein (ACP) domains, indicating the biosynthesis is likely to employ an unconventional and cryptic off-loading mechanism that attaches glycine to the polyene-polyol chain via an intermolecular amidation reaction.

Keywords
biosynthesis; biosynthetic gene cluster; guanidine; ketosynthase; polyketide synthase.
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