Methanoarchaeal sulfolactate dehydrogenase: prototype of a new family of NADH-dependent enzymes

EMBO J. 2004 Mar 24;23(6):1234-44. doi: 10.1038/sj.emboj.7600147. Epub 2004 Mar 11.


The crystal structure of the sulfolactate dehydrogenase from the hyperthermophilic and methanogenic archaeon Methanocaldococcus jannaschii was solved at 2.5 A resolution (PDB id. 1RFM). The asymmetric unit contains a tetramer of tight dimers. This structure, complexed with NADH, does not contain a cofactor-binding domain with 'Rossmann-fold' topology. Instead, the tertiary and quaternary structures indicate a novel fold. The NADH is bound in an extended conformation in each active site, in a manner that explains the pro-S specificity. Cofactor binding involves residues belonging to both subunits within the tight dimers, which are therefore the smallest enzymatically active units. The protein was found to be a homodimer in solution by size-exclusion chromatography, analytical ultracentrifugation and small-angle neutron scattering. Various compounds were tested as putative substrates. The results indicate the existence of a substrate discrimination mechanism, which involves electrostatic interactions. Based on sequence homology and phylogenetic analyses, several other enzymes were classified as belonging to this novel family of homologous (S)-2-hydroxyacid dehydrogenases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Dimerization
  • Escherichia coli / enzymology
  • Evolution, Molecular
  • Lactose / chemistry
  • Lactose / metabolism*
  • Methanococcales / enzymology*
  • Methanococcales / genetics
  • Models, Molecular
  • NAD / metabolism*
  • Oxidoreductases / chemistry
  • Oxidoreductases / classification
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism*
  • Phylogeny
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Solutions
  • Structural Homology, Protein
  • Substrate Specificity
  • Sugar Alcohol Dehydrogenases / chemistry
  • Sugar Alcohol Dehydrogenases / metabolism
  • Sulfur / chemistry*


  • Solutions
  • NAD
  • Sulfur
  • Oxidoreductases
  • Sugar Alcohol Dehydrogenases
  • 2,3-diketo-L-gulonate reductase
  • Lactose