ArticleApplied and environmental microbiology2014
Operon for biosynthesis of lipstatin, the Beta-lactone inhibitor of human pancreatic lipase.
Article in Applied and environmental microbiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 38 citations in OpenAlex.
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- Genomic insights and metabolic profiling of gut commensal Luoshenia tenuis at strain level.NPJ biofilms and microbiomes · 2025Article
- Enhanced Production of Lipstatin Through NTG Treatment of Streptomyces toxytricini KD18 at 5 L Bioreactor Level.Applied biochemistry and biotechnology · 2023Article
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- Article
- Global analysis of adenylate-forming enzymes reveals β-lactone biosynthesis pathway in pathogenicThe Journal of biological chemistry · 2020Article
- Microbial lipases and their industrial applications: a comprehensive review.Microbial cell factories · 2020Review
- Article
- Recent Advances in Enzymatic Complexity Generation: Cyclization Reactions.Biochemistry · 2018Review
- Development and Optimization of a High-Throughput Screening Assay for Rapid Evaluation of Lipstatin Production by Streptomyces Strains.Current microbiology · 2018Article
- β-Lactone formation during product release from a nonribosomal peptide synthetase.Nature chemical biology · 2017Article
- Active Multienzyme Assemblies for Long-Chain Olefinic Hydrocarbon Biosynthesis.Journal of bacteriology · 2017Article
- β-Lactone Synthetase Found in the Olefin Biosynthesis Pathway.Biochemistry · 2017Article
- StreptomeDB 2.0--an extended resource of natural products produced by streptomycetes.Nucleic acids research · 2016Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Lipstatin, isolated from Streptomyces toxytricini as a potent and selective inhibitor of human pancreatic lipase, is a precursor for tetrahydrolipstatin (also known as orlistat, Xenical, and Alli), the only FDA-approved antiobesity medication for long-term use. Lipstatin features a 2-hexyl-3,5-dihydroxy-7,10-hexadecadienoic-β-lactone structure with an N-formyl-l-leucine group attached as an ester to the 5-hydroxy group. It has been suggested that the α-branched 3,5-dihydroxy fatty acid β-lactone moiety of lipstatin in S. toxytricini is derived from Claisen condensation between two fatty acid substrates, which are derived from incomplete oxidative degradation of linoleic acid based on feeding experiments. In this study, we identified a six-gene operon (lst) that was essential for the biosynthesis of lipstatin by large-deletion, complementation, and single-gene knockout experiments. lstA, lstB, and lstC, which encode two β-ketoacyl-acyl carrier protein synthase III homologues and an acyl coenzyme A (acyl-CoA) synthetase homologue, were indicated to be responsible for the generation of the α-branched 3,5-dihydroxy fatty acid backbone. Subsequently, the nonribosomal peptide synthetase (NRPS) gene lstE and the putative formyltransferase gene lstF were involved in decoration of the α-branched 3,5-dihydroxy fatty acid chain with an N-formylated leucine residue. Finally, the 3β-hydroxysteroid dehydrogenase-homologous gene lstD might be responsible for the reduction of the β-keto group of the biosynthetic intermediate, thereby facilitating the formation of the unique β-lactone ring.
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