Insights into methyltransferase specificity and bioactivity of derivatives of the antibiotic plantazolicin
| Autor: | Douglas A. Mitchell, Yue Hao, Patricia M. Blair, Satish K. Nair, Abhishek Sharma |
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| Rok vydání: | 2015 |
| Předmět: |
Plantazolicin
Methyltransferase Stereochemistry Molecular Sequence Data Peptide Crystallography X-Ray Biochemistry Article Substrate Specificity chemistry.chemical_compound Residue (chemistry) Amino Acid Sequence Peptide sequence chemistry.chemical_classification Natural product biology Molecular Structure Sequence Homology Amino Acid Chemistry General Medicine Methyltransferases biology.organism_classification Bacillus anthracis Anti-Bacterial Agents Kinetics Enzyme Molecular Medicine Oligopeptides |
| Zdroj: | ACS chemical biology. 10(5) |
| ISSN: | 1554-8937 |
| Popis: | Peptide antibiotics represent a class of conformationally constrained natural products of growing pharmaceutical interest. Plantazolicin (PZN) is a linear, polyheterocyclic natural product with highly selective and potent activity against the anthrax-causing bacterium, Bacillus anthracis. The bioactivity of PZN is contingent on dimethylation of its N-terminal Arg residue by an S-adenosylmethionine-dependent methyltransferase. Here, we explore the substrate tolerances of two homologous PZN methyltransferases by carrying out kinetic analyses of the enzymes against a synthetic panel of truncated PZN analogs containing the N-terminal Arg residue. X-ray cocrystal structures of the PZN methyltransferases with each of these heterocycle-containing substrates provide a rationale for understanding the strict substrate specificity of these enzymes. Kinetic studies of structure-guided, site-specific variants allowed for the assignment of residues governing catalysis and substrate scope. Microbiological testing further revealed that upon dimethylation of the N-terminal Arg, a pentaheterocyclized PZN analog retained potent anti-B. anthracis activity, nearly equal to that of full-length PZN. These studies may be useful in the biosynthetic engineering of natural product analogs with different bioactivity profiles, as demonstrated by our identification of a truncated plantazolicin derivative that is active against methicillin-resistant Staphylococcus aureus (MRSA). |
| Databáze: | OpenAIRE |
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