Crystal structure of 2-oxoisovalerate and dehydrogenase and the architecture of 2-oxo acid dehydrogenase multienzyme complexes

Nat Struct Biol. 1999 Aug;6(8):785-92. doi: 10.1038/11563.


The family of giant multienzyme complexes metabolizing pyruvate, 2-oxoglutarate, branched-chain 2-oxo acids or acetoin contains several of the largest and most sophisticated protein assemblies known, with molecular masses between 4 and 10 million Da. The principal enzyme components, E1, E2 and E3, are present in numerous copies and utilize multiple cofactors to catalyze a directed sequence of reactions via substrate channeling. The crystal structure of a heterotetrameric (alpha2beta2) E1, 2-oxoisovalerate dehydrogenase from Pseudomonas putida, reveals a tightly packed arrangement of the four subunits with the beta2-dimer held between the jaws of a 'vise' formed by the alpha2-dimer. A long hydrophobic channel, suitable to accommodate the E2 lipoyl-lysine arm, leads to the active site, which contains the cofactor thiamin diphosphate (ThDP) and an inhibitor-derived covalent modification of a histidine side chain. The E1 structure, together with previous structural information on E2 and E3, completes the picture of the shared architectural features of these enormous macromolecular assemblies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
  • Acylation
  • Binding Sites
  • Crystallography, X-Ray
  • Hemiterpenes
  • Keto Acids / chemistry*
  • Ketone Oxidoreductases / chemistry*
  • Models, Molecular
  • Multienzyme Complexes / chemistry*
  • Multienzyme Complexes / metabolism
  • Protein Binding
  • Protein Conformation
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Thioctic Acid / analogs & derivatives
  • Thioctic Acid / metabolism


  • Hemiterpenes
  • Keto Acids
  • Multienzyme Complexes
  • Recombinant Proteins
  • Thioctic Acid
  • alpha-ketoisovalerate
  • lipoamide
  • Ketone Oxidoreductases
  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)

Associated data

  • PDB/1QSO