Carbon-sulfur bond-forming reaction catalysed by the radical SAM enzyme HydE

Nat Chem. 2016 May;8(5):491-500. doi: 10.1038/nchem.2490. Epub 2016 Apr 4.


Carbon-sulfur bond formation at aliphatic positions is a challenging reaction that is performed efficiently by radical S-adenosyl-L-methionine (SAM) enzymes. Here we report that 1,3-thiazolidines can act as ligands and substrates for the radical SAM enzyme HydE, which is involved in the assembly of the active site of [FeFe]-hydrogenase. Using X-ray crystallography, in vitro assays and NMR spectroscopy we identified a radical-based reaction mechanism that is best described as the formation of a C-centred radical that concomitantly attacks the sulfur atom of a thioether. To the best of our knowledge, this is the first example of a radical SAM enzyme that reacts directly on a sulfur atom instead of abstracting a hydrogen atom. Using theoretical calculations based on our high-resolution structures we followed the evolution of the electronic structure from SAM through to the formation of S-adenosyl-L-cysteine. Our results suggest that, at least in this case, the widely proposed and highly reactive 5'-deoxyadenosyl radical species that triggers the reaction in radical SAM enzymes is not an isolable intermediate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbon / chemistry
  • Catalysis
  • Catalytic Domain
  • Clostridium acetobutylicum / enzymology
  • Cysteine / analogs & derivatives
  • Cysteine / chemistry
  • Free Radicals / chemistry
  • Ligands
  • Models, Chemical
  • Oxidoreductases Acting on Sulfur Group Donors / chemistry*
  • Quantum Theory
  • S-Adenosylmethionine / chemistry
  • Sulfur / chemistry
  • Thermotoga maritima / enzymology
  • Thiazolidines / chemistry*


  • Free Radicals
  • Ligands
  • Thiazolidines
  • Sulfur
  • Carbon
  • S-Adenosylmethionine
  • Oxidoreductases Acting on Sulfur Group Donors
  • Cysteine