Document Detail

The chemical versatility of natural-product assembly lines.
MedLine Citation:
PMID:  17506516     Owner:  NLM     Status:  MEDLINE    
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.
Christopher T Walsh
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Review     Date:  2007-05-17
Journal Detail:
Title:  Accounts of chemical research     Volume:  41     ISSN:  1520-4898     ISO Abbreviation:  Acc. Chem. Res.     Publication Date:  2008 Jan 
Date Detail:
Created Date:  2008-01-15     Completed Date:  2008-05-28     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0157313     Medline TA:  Acc Chem Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4-10     Citation Subset:  IM    
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
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MeSH Terms
Biological Factors / chemical synthesis,  chemistry*
Drug Design
Enzymes / chemistry
Macrolides / chemical synthesis,  chemistry*
Molecular Conformation
Peptides / chemical synthesis,  chemistry*
Grant Support
Reg. No./Substance:
0/Biological Factors; 0/Enzymes; 0/Macrolides; 0/Peptides

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