Minimization of the thiolactomycin biosynthetic pathway reveals that the cytochrome p450 enzyme tlmf is required for five-membered thiolactone ring formation

TitleMinimization of the thiolactomycin biosynthetic pathway reveals that the cytochrome p450 enzyme tlmf is required for five-membered thiolactone ring formation
Publication TypeJournal Article
Year of Publication2017
AuthorsTang X.Y, Li J., Moore BS
JournalChembiochem
Volume18
Pagination1072-1076
Date Published2017/06
Type of ArticleArticle
ISBN Number1439-4227
Accession NumberWOS:000403789400005
Keywordsagents; analogs; antibiotic thiolactomycin; assembly lines; biosynthesis; escherichia-coli; fatty acid synthase inhibitor; fatty-acid synthases; inhibition; natural-products; polyketide; potential antimalarial; ring; Salinispora; thiolactone; thiotetronate antibiotics
Abstract

Thiolactomycin (TLM) belongs to a class of rare and unique thiotetronate antibiotics that inhibit bacterial fatty acid synthesis. Although this group of natural product antibiotics was first discovered over 30 years ago, the study of TLM biosynthesis remains in its infancy. We recently discovered the biosynthetic gene cluster (BGC) for TLM from the marine bacterium Salinispora pacifica CNS-863. Here, we report the investigation of TLM biosynthetic logic through mutagenesis and comparative metabolic analyses. Our results revealed that only four genes (tlmF, tlmG, tlmH, and tlmI) are required for the construction of the characteristic -thiolactone skeleton of this class of antibiotics. We further showed that the cytochrome P450 TlmF does not directly participate in sulfur insertion and C-S bond formation chemistry but rather in the construction of the five-membered thiolactone ring as, upon its deletion, we observed the alternative production of the six-membered -thiolactomycin. Our findings pave the way for future biochemical investigation of the biosynthesis of this structurally unique group of thiotetronic acid natural products.

DOI10.1002/cbic.201700090
Short TitleChemBioChem
Student Publication: 
No
Research Topics: 
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