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The Chemical Versatility of Natural-Product Assembly Lines

Microbial natural products of both polyketide and nonribosomal peptide origin have been and continue to be important therapeutic agents as antibiotics, immunosupressants, and antitumor drugs. Because the biosynthetic genes for these metabolites are clustered for coordinate regulation, the sequencing...

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Published in:Accounts of chemical research 2008-01, Vol.41 (1), p.4-10
Main Author: Walsh, Christopher T
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Language:English
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description Microbial natural products of both polyketide and nonribosomal peptide origin have been and continue to be important therapeutic agents as antibiotics, immunosupressants, and antitumor drugs. Because the biosynthetic genes for these metabolites are clustered for coordinate regulation, the sequencing of bacterial genomes continues to reveal unanticipated biosynthetic capacity for novel natural products. The re-engineering of pathways for such secondary metabolites to make novel molecular variants will be enabled by understanding of the chemical logic and protein machinery in the producer microbes. This Account analyzes the chemical principles and molecular logic that allows simple primary metabolite building blocks to be converted to complex architectural scaffolds of polyketides (PK), nonribosomal peptides (NRP), and NRP-PK hybrids. The first guiding principle is that PK and NRP chains are assembled as thioseters tethered to phosphopantetheinyl arms of carrier proteins that serve as thiotemplates for chain elongation. The second principle is that gate keeper protein domains select distinct monomers to be activated and incorporated with positional specificity into the growing natural product chains. Chain growth is via thioclaisen condensations for PK and via amide bond formation for elongating NRP chains. Release of the full length acyl/peptidyl chains is mediated by thioesterases, some of which catalyze hydrolysis while others catalyze regiospecific macrocyclization to build in conformational constraints. Tailoring of PK and NRP chains, by acylation, alkylation, glycosylation, and oxidoreduction, occurs both during tethered chain growth and after thioesterase-mediated release. Analysis of the types of protein domains that carry out chain initiation, elongation, tailoring, and termination steps gives insight into how NRP and PK biosynthetic assembly lines can be redirected to make novel molecules.
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source American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list)
subjects Biological Factors - chemical synthesis
Biological Factors - chemistry
Cyclization
Drug Design
Enzymes - chemistry
Hydrolysis
Macrolides - chemical synthesis
Macrolides - chemistry
Molecular Conformation
Peptides - chemical synthesis
Peptides - chemistry
Stereoisomerism
title The Chemical Versatility of Natural-Product Assembly Lines
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