Discovery of the Biosynthetic Machinery for Stravidins, Biotin Antimetabolites
| Autor: | Neil L. Kelleher, Rana Montaser |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Peptide Biosynthesis
0301 basic medicine Streptavidin Antimetabolites Decarboxylation Biotin 01 natural sciences Biochemistry Streptomyces Article 03 medical and health sciences chemistry.chemical_compound Biosynthesis Drug Discovery Gene cluster Chorismic acid Amino Acid Sequence Gene Base Sequence biology 010405 organic chemistry Aminobutyrates General Medicine biology.organism_classification Anti-Bacterial Agents 0104 chemical sciences 030104 developmental biology chemistry Multigene Family Molecular Medicine Peptides |
| Zdroj: | ACS Chem Biol |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/acschembio.9b00890 |
| Popis: | Stravidins are peptide antibiotics produced by Streptomyces spp. Their antibacterial activity derives from an unusual amiclenomycin monomer, the warhead that inhibits biotin biosynthesis. Despite being discovered over five decades ago, stravidin biosynthesis has remained a mystery. Using our “metabologenomics” platform, we discover new stravidin analogues and identify the novel biosynthetic machinery responsible for their production. Analysis of the newly identified biosynthetic gene cluster (BGC) indicates the unusual amiclenomycin warhead is derived from chorismic acid, with initial steps similar to those involved in p-amino phenylalanine biosynthesis. However, a distinctive decarboxylation retains the nonaromatic character of a key ring and precedes a one-carbon extension to afford the warhead in its bioactive, untriggered state. Strikingly, we also identified two streptavidin genes flanking the new stravidin BGC reported here. This aligns with the known synergistic activity between the biotin-binding activity of streptavidin and the stravidins to antagonize both biotin biogenesis and bacterial growth. |
| Databáze: | OpenAIRE |
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