4.6 Review

Biosynthetic Cyclization Catalysts for the Assembly of Peptide and Polyketide Natural Products

Journal

CHEMCATCHEM
Volume 13, Issue 9, Pages 2095-2116

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/cctc.202001886

Keywords

Enzymes; Natural Products; Biocatalysis; Polyketide Synthase; Nonribosomal Peptide Synthetase

Funding

  1. NIGMS NIH HHS [R35 GM118101] Funding Source: Medline

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This review explores the general cyclization mechanism of TE domain in NRPS and PKS, including oligomerization and CLCs. It also discusses other cyclization catalysts such as C-T domains, R domains, R-D domains, Dieckmann cyclases, among others. The diversity of cyclization catalysts highlighted in the studies for the production of biologically relevant, complex cyclic natural products and related compounds is summarized here.
Many biologically active natural products are synthesized by nonribosomal peptide synthetases (NRPSs), polyketide synthases (PKSs) and their hybrids. These megasynthetases are comprised of modules which are subdivided into distinct catalytic domains that allow for substrate initiation, chain extension, processing and termination. At the end of a module, a terminal domain, usually a thioesterase (TE), is responsible for catalyzing the release of the NRPS or PKS as a linear or cyclized product. In this Review, we address the general cyclization mechanism of the TE domain, including oligomerization and the fungal C-C bond forming Claisen-like cyclases (CLCs). Additionally, we include examples of cyclization catalysts acting within or at the end of a module. Furthermore, condensation-like (C-T) domains, terminal reductase (R) domains, reductase-like domains that catalyze Dieckmann condensation (R-D), thioesterase-like Dieckmann cyclases, trans-acting TEs from the penicillin binding protein (PBP) enzyme family, product template (PT) domains and others will also be reviewed. The studies summarized here highlight the remarkable diversity of NRPS and PKS cyclization catalysts for the production of biologically relevant, complex cyclic natural products and related compounds.

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