ArticleProceedings of the National Academy of Sciences of the United States of America2015
Consecutive radical S-adenosylmethionine methylations form the ethyl side chain in thienamycin biosynthesis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 89 citations in OpenAlex.
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- Stereochemical course of cobalamin-dependent radical SAM methylation by TokK and ThnK.RSC chemical biology · 2022Article
- Biosynthesis of 3-thia-α-amino acids on a carrier peptide.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Cobalamin-Dependent RadicalACS bio & med chem Au · 2022Review
- The Atypical Cobalamin-DependentJournal of the American Chemical Society · 2022Article
- Evolution of Methods for the Study of Cobalamin-Dependent Radical SAM Enzymes.ACS bio & med chem Au · 2022Article
- Structure of a BNature · 2022Article
- Crystallographic snapshots of a BNature · 2022Article
- Studies of GenK and OxsB, two BMethods in enzymology · 2022Article
- Purification and characterization of sequential cobalamin-dependent radical SAM methylases ThnK and TokK in carbapenem β-lactam antibiotic biosynthesis.Methods in enzymology · 2022Article
- Towards a Synthetic Biology Toolset for Metallocluster Enzymes in Biosynthetic Pathways: What We Know and What We Need.Molecules (Basel, Switzerland) · 2021Review
- Overall Retention of Methyl Stereochemistry during BBiochemistry · 2021Article
- Acyl Donor Stringency and Dehydroaminoacyl Intermediates in β-Lactam Formation by a Non-ribosomal Peptide Synthetase.ACS chemical biology · 2021Article
- Biosynthesis of Oxetanocin-A Includes a BBiochemistry · 2021Article
- Biosynthesis of the Nuclear Factor of Activated T Cells Inhibitor NFAT-133 inACS chemical biology · 2020Article
- Methylations in complex carbapenem biosynthesis are catalyzed by a single cobalamin-dependent radical S-adenosylmethionine enzyme.Chemical communications (Cambridge, England) · 2019Article
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8 authors at 3 institutions in 1 country.
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Abstract
Despite their broad anti-infective utility, the biosynthesis of the paradigm carbapenem antibiotic, thienamycin, remains largely unknown. Apart from the first two steps shared with a simple carbapenem, the pathway sharply diverges to the more structurally complex members of this class of β-lactam antibiotics, such as thienamycin. Existing evidence points to three putative cobalamin-dependent radical S-adenosylmethionine (RS) enzymes, ThnK, ThnL, and ThnP, as potentially being responsible for assembly of the ethyl side chain at C6, bridgehead epimerization at C5, installation of the C2-thioether side chain, and C2/3 desaturation. The C2 substituent has been demonstrated to be derived by stepwise truncation of CoA, but the timing of these events with respect to C2-S bond formation is not known. We show that ThnK of the three apparent cobalamin-dependent RS enzymes performs sequential methylations to build out the C6-ethyl side chain in a stereocontrolled manner. This enzymatic reaction was found to produce expected RS methylase coproducts S-adenosylhomocysteine and 5'-deoxyadenosine, and to require cobalamin. For double methylation to occur, the carbapenam substrate must bear a CoA-derived C2-thioether side chain, implying the activity of a previous sulfur insertion by an as-yet unidentified enzyme. These insights allow refinement of the central steps in complex carbapenem biosynthesis.
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