Paramagnetic intermediates generated by radical S-adenosylmethionine (SAM) enzymes.

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  • Author(s): Stich TA;Stich TA; Myers WK; Britt RD
  • Source:
    Accounts of chemical research [Acc Chem Res] 2014 Aug 19; Vol. 47 (8), pp. 2235-43. Date of Electronic Publication: 2014 Jul 03.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 0157313 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4898 (Electronic) Linking ISSN: 00014842 NLM ISO Abbreviation: Acc Chem Res Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, American Chemical Society.
    • Subject Terms:
      Hydrogenase/*metabolism ; Intramolecular Transferases/*metabolism ; Iron-Sulfur Proteins/*metabolism ; Methyltransferases/*metabolism ; S-Adenosylmethionine/*metabolism ; Sulfurtransferases/*metabolism; Biocatalysis ; Catalytic Domain ; Electron Spin Resonance Spectroscopy ; Free Radicals/chemistry ; Free Radicals/metabolism ; Intramolecular Transferases/chemistry ; Oxidation-Reduction ; Quantum Theory ; S-Adenosylmethionine/chemistry ; Sulfurtransferases/chemistry
    • Abstract:
      A [4Fe-4S](+) cluster reduces a bound S-adenosylmethionine (SAM) molecule, cleaving it into methionine and a 5'-deoxyadenosyl radical (5'-dA(•)). This step initiates the varied chemistry catalyzed by each of the so-called radical SAM enzymes. The strongly oxidizing 5'-dA(•) is quenched by abstracting a H-atom from a target species. In some cases, this species is an exogenous molecule of substrate, for example, L-tyrosine in the [FeFe] hydrogenase maturase, HydG. In other cases, the target is a proteinaceous residue as in all the glycyl radical forming enzymes. The generation of this initial radical species and the subsequent chemistry involving downstream radical intermediates is meticulously controlled by the enzyme so as to prevent unwanted reactions. But the manner in which this control is exerted is unknown. Electron paramagnetic resonance (EPR) spectroscopy has proven to be a valuable tool used to gain insight into these mechanisms. In this Account, we summarize efforts to trap such radical intermediates in radical SAM enzymes and highlight four examples in which EPR spectroscopic results have shed significant light on the corresponding mechanism. For lysine 2,3-aminomutase, nearly each possible intermediate, from an analogue of the initial 5'-dA(•) to the product radical L-β-lysine, has been explored. A paramagnetic intermediate observed in biotin synthase is shown to involve an auxiliary [FeS] cluster whose bridging sulfide is a co-substrate for the final step in the biosynthesis of vitamin B7. In HydG, the L-tyrosine substrate is converted in unprecedented fashion to a 4-oxidobenzyl radical on the way to generating CO and CN(-) ligands for the [FeFe] cluster of hydrogenase. And finally, EPR has confirmed a mechanistic proposal for the antibiotic resistance protein Cfr, which methylates the unactivated sp(2)-hybridized C8-carbon of an adenosine base of 23S ribosomal RNA. These four systems provide just a brief survey of the ever-growing set of radical SAM enzymes. The diverse chemistries catalyzed by these enzymes make them an intriguing target for continuing study, and EPR spectroscopy, in particular, seems ideally placed to contribute to our understanding.
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    • Grant Information:
      R01 GM104543 United States GM NIGMS NIH HHS; GM104543 United States GM NIGMS NIH HHS
    • Accession Number:
      0 (Free Radicals)
      0 (Iron-Sulfur Proteins)
      7LP2MPO46S (S-Adenosylmethionine)
      EC 1.12.- (iron hydrogenase)
      EC 1.12.7.2 (Hydrogenase)
      EC 2.1.1.- (Methyltransferases)
      EC 2.8.1.- (Sulfurtransferases)
      EC 2.8.1.6 (biotin synthetase)
      EC 5.4.- (Intramolecular Transferases)
      EC 5.4.3.2 (lysine 2,3-aminomutase)
    • Publication Date:
      Date Created: 20140704 Date Completed: 20150827 Latest Revision: 20211021
    • Publication Date:
      20250114
    • Accession Number:
      PMC4139163
    • Accession Number:
      10.1021/ar400235n
    • Accession Number:
      24991701