Issue 3, 2003

Enzymology of acyl chain macrocyclization in natural product biosynthesis

Abstract

Polyketides and nonribosomal peptides constitute a large and diverse set of natural products with biological activity in microbial survival and pathogenesis, as well as broad pharmacological utility as antineoplastics, antibiotics or immunosupressants. These molecules are biosynthesized by the ordered condensation of monomer building blocks, acyl-CoAs or amino acids, leading to construction of linear acyl chains. Many of these natural products are constrained to their bioactive conformations by macrocyclization whereby, in one of the terminal steps of biosynthesis, parts of the molecule distant in the constructed linear acyl chain are covalently linked to one another. Typically, macrocyclization is catalyzed by a thioesterase domain at the C-terminal end of the biosynthetic assembly line, although alternative strategies are known. The enzymology of these macrocyclization catalysts, their structure, mechanism, and catalytic versatility, is the subject of this review. The diversity of macrocyclic structures accessed by enzyme catalyzed cyclization of linear acyl chains as well as their inherent substrate tolerance suggests their potential utility in reprogramming natural product biosynthesis pathways or accessing novel macrocyclic structures.

Graphical abstract: Enzymology of acyl chain macrocyclization in natural product biosynthesis

Article information

Article type
Feature Article
Submitted
28 Aug 2002
Accepted
06 Nov 2002
First published
22 Nov 2002

Chem. Commun., 2003, 297-307

Enzymology of acyl chain macrocyclization in natural product biosynthesis

R. M. Kohli and C. T. Walsh, Chem. Commun., 2003, 297 DOI: 10.1039/B208333G

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