Explorations of catalytic domains in non-ribosomal peptide synthetase enzymology

Many pharmaceuticals on the market today belong to a large class of natural products called nonribosomal peptides (NRPs). Originating from bacteria and fungi, these peptide-based natural products consist not only of the 20 canonical L-amino acids, but also non-proteinogenic amino acids, heterocyclic...

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Veröffentlicht in:Natural product reports Jg. 29; H. 10; S. 1074
Hauptverfasser: Hur, Gene H, Vickery, Christopher R, Burkart, Michael D
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England 01.01.2012
Schlagworte:
Bacteria - chemistry
Catalytic Domain
Fungi - chemistry
Models, Molecular
Peptide Biosynthesis, Nucleic Acid-Independent
Peptide Synthases - chemistry
Peptide Synthases - metabolism
Peptides - metabolism
Protein Conformation
ISSN:1460-4752, 1460-4752
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Zusammenfassung:Many pharmaceuticals on the market today belong to a large class of natural products called nonribosomal peptides (NRPs). Originating from bacteria and fungi, these peptide-based natural products consist not only of the 20 canonical L-amino acids, but also non-proteinogenic amino acids, heterocyclic rings, sugars, and fatty acids, generating tremendous chemical diversity. As a result, these secondary metabolites exhibit a broad array of bioactivity, ranging from antimicrobial to anticancer. The biosynthesis of these complex compounds is carried out by large multimodular megaenzymes called nonribosomal peptide synthetases (NRPSs). Each module is responsible for incorporation of a monomeric unit into the natural product peptide and is composed of individual domains that perform different catalytic reactions. Biochemical and bioinformatic investigations of these enzymes have uncovered the key principles of NRP synthesis, expanding the pharmaceutical potential of their enzymatic processes. Progress has been made in the manipulation of this biosynthetic machinery to develop new chemoenzymatic approaches for synthesizing novel pharmaceutical agents with increased potency. This review focuses on the recent discoveries and breakthroughs in the structural elucidation, molecular mechanism, and chemical biology underlying the discrete domains within NRPSs.
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ISSN:1460-4752
1460-4752
DOI:10.1039/c2np20025b