ArticleProceedings of the National Academy of Sciences of the United States of America2008
Four enzymes define the incorporation of coenzyme A in thienamycin biosynthesis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 34 citations in OpenAlex.
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- Evolution of Methods for the Study of Cobalamin-Dependent Radical SAM Enzymes.ACS bio & med chem Au · 2022Article
- Methylations in complex carbapenem biosynthesis are catalyzed by a single cobalamin-dependent radical S-adenosylmethionine enzyme.Chemical communications (Cambridge, England) · 2019Article
- Roles of 2-oxoglutarate oxygenases and isopenicillin N synthase in β-lactam biosynthesis.Natural product reports · 2018Review
- Convergent biosynthetic pathways to β-lactam antibiotics.Current opinion in chemical biology · 2016Review
- Linking Biosynthetic Gene Clusters to their Metabolites via Pathway- Targeted Molecular Networking.Current topics in medicinal chemistry · 2016Review
- Consecutive radical S-adenosylmethionine methylations form the ethyl side chain in thienamycin biosynthesis.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- β-Lactam formation by a non-ribosomal peptide synthetase during antibiotic biosynthesis.Nature · 2015Article
- Exploring the role of conformational heterogeneity in cis-autoproteolytic activation of ThnT.Biochemistry · 2014Article
- Identification and characterization of the carbapenem MM 4550 and its gene cluster in Streptomyces argenteolus ATCC 11009.Chembiochem : a European journal of chemical biology · 2014Article
- Stereocontrolled syntheses of peptide thioesters containing modified seryl residues as probes of antibiotic biosynthesis.The Journal of organic chemistry · 2013Article
- Autoproteolytic activation of ThnT results in structural reorganization necessary for substrate binding and catalysis.Journal of molecular biology · 2012Article
- Insights into cis-autoproteolysis reveal a reactive state formed through conformational rearrangement.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Definition of the common and divergent steps in carbapenem β-lactam antibiotic biosynthesis.Chembiochem : a European journal of chemical biology · 2011Article
- Mutational analysis of the thienamycin biosynthetic gene cluster from Streptomyces cattleya.Antimicrobial agents and chemotherapy · 2011Article
- Non-heme iron oxygenases generate natural structural diversity in carbapenem antibiotics.Journal of the American Chemical Society · 2010Article
- A conserved lysine in beta-lactam synthetase assists ring cyclization: Implications for clavam and carbapenem biosynthesis.Chembiochem : a European journal of chemical biology · 2009Article
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5 authors at 1 institution in 1 country.
Funding
Abstract
The enzymatic activities of three proteins encoded by the thienamycin gene cluster of Streptomyces cattleya (ThnR, ThnH, and ThnT) have been shown to incrementally cleave CoA to afford the active side-chain component of the beta-lactam antibiotic thienamycin. These results supersede proposals based on earlier radiochemical incorporation experiments. For 20 years it has been thought that cysteine was directly incorporated into the antibiotic. Specific, stepwise truncation of CoA to 4-phosphopantetheine, pantetheine, and finally cysteamine was observed with ThnR, ThnH, and ThnT, respectively, in a series of coupled enzymatic assays. Pantetheinylated carbapenams were synthesized to address possible thienamycin biosynthetic intermediates and were shown to be effective substrates for the pantetheine-cleaving enzyme ThnT. Finally, a fourth gene, thnF, was shown to encode a protein capable of N-acetylating a model compound containing cysteamine in the presence of acetyl-CoA, consistent with the production of the S. cattleya cometabolite, N-acetylthienamycin. Taken together, these four enzymes are proposed to siphon CoA from primary metabolism to create the side chains for the predominant S. cattleya carbapenems, thienamycin and N-acetylthienamycin, in a process likely to be general for the broader class of these antibiotics.
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