Radical SAM Enzyme Spore Photoproduct Lyase: Properties of the Ω Organometallic Intermediate and Identification of Stable Protein Radicals Formed during Substrate-Free Turnover

J Am Chem Soc. 2020 Oct 28;142(43):18652-18660. doi: 10.1021/jacs.0c08585. Epub 2020 Oct 15.

Abstract

Spore photoproduct lyase is a radical S-adenosyl-l-methionine (SAM) enzyme with the unusual property that addition of SAM to the [4Fe-4S]1+ enzyme absent substrate results in rapid electron transfer to SAM with accompanying homolytic S-C5' bond cleavage. Herein, we demonstrate that this unusual reaction forms the organometallic intermediate Ω in which the unique Fe atom of the [4Fe-4S] cluster is bound to C5' of the 5'-deoxyadenosyl radical (5'-dAdo). During catalysis, homolytic cleavage of the Fe-C5' bond liberates 5'-dAdo for reaction with substrate, but here, we use Ω formation without substrate to determine the thermal stability of Ω. The reaction of Geobacillus thermodenitrificans SPL (GtSPL) with SAM forms Ω within ∼15 ms after mixing. By monitoring the decay of Ω through rapid freeze-quench trapping at progressively longer times we find an ambient temperature decay time of the Ω Fe-C5' bond of τ ≈ 5-6 s, likely shortened by enzymatic activation as is the case with the Co-C5' bond of B12. We have further used hand quenching at times up to 10 min, and thus with multiple SAM turnovers, to probe the fate of the 5'-dAdo radical liberated by Ω. In the absence of substrate, Ω undergoes low-probability conversion to a stable protein radical. The WT enzyme with valine at residue 172 accumulates a Val; mutation of Val172 to isoleucine or cysteine results in accumulation of an Ile or Cys radical, respectively. The structures of the radical in WT, V172I, and V172C variants have been established by detailed EPR/DFT analyses.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Catalytic Domain
  • Density Functional Theory
  • Deoxyadenosines / chemistry
  • Electron Spin Resonance Spectroscopy
  • Free Radicals / chemistry*
  • Geobacillus / enzymology
  • Iron-Sulfur Proteins / chemistry
  • Models, Molecular
  • Proteins / chemistry*
  • Proteins / genetics
  • Proteins / metabolism
  • S-Adenosylmethionine / chemistry*
  • S-Adenosylmethionine / metabolism

Substances

  • Deoxyadenosines
  • Free Radicals
  • Iron-Sulfur Proteins
  • Proteins
  • S-Adenosylmethionine
  • spore photoproduct lyase

Supplementary concepts

  • Geobacillus thermodenitrificans