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Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
Published on: October 25, 2013
Polyketide and nonribosomal peptide antibiotics: modularity and versatility.
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. christopher_walsh@hms.harvard.edu
Science (New York, N.Y.)
|March 20, 2004
Summary
Tailoring enzymes guide the formation of biologically active polyketide (PK) and nonribosomal peptide (NRP) natural products. Reprogramming these enzymes offers a path to novel antibiotics.
Area of Science:
- Biochemistry
- Molecular Biology
- Natural Product Chemistry
Background:
- Polyketides (PK) and nonribosomal peptides (NRP) are complex natural products synthesized by large, multimodular enzyme complexes.
- Tailoring enzymes, encoded by gene clusters, introduce structural modifications crucial for biological activity.
- These modifications include cyclizations, oxidations, and cross-linking, leading to diverse molecular architectures.
Purpose of the Study:
- To elucidate the roles of tailoring enzymes in the biosynthesis of PK and NRP natural products.
- To explore the potential of reprogramming these enzymatic pathways for novel antibiotic discovery.
Main Methods:
- Analysis of gene clusters encoding PK and NRP assembly lines and associated tailoring enzymes.
- Investigating the enzymatic mechanisms of cyclization and oxidation reactions.
- Bioinformatic analysis of enzyme modularity and substrate permissivity.
Main Results:
- Tailoring enzymes introduce cyclization constraints during PK and NRP biosynthesis, including heterocyclizations (thiazoles, oxazoles) and macrocyclizations.
- Post-assembly line enzymatic oxidations create complex, cross-linked architectures.
- Evidence suggests modularity and enzyme permissivity allow for pathway reprogramming.
Conclusions:
- Tailoring enzymes are essential for generating the bioactive conformations of PK and NRP natural products.
- The inherent modularity and flexibility of these biosynthetic pathways present opportunities for engineering novel antibiotics with enhanced properties.
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