A molecular switch and proton wire synchronize the active sites in thiamine enzymes

Science. 2004 Oct 29;306(5697):872-6. doi: 10.1126/science.1101030.


Thiamine diphosphate (ThDP) is used as a cofactor in many key metabolic enzymes. We present evidence that the ThDPs in the two active sites of the E1 (EC component of the pyruvate dehydrogenase complex communicate over a distance of 20 angstroms by reversibly shuttling a proton through an acidic tunnel in the protein. This "proton wire" permits the co-factors to serve reciprocally as general acid/base in catalysis and to switch the conformation of crucial active-site peptide loops. This synchronizes the progression of chemical events and can account for the oligomeric organization, conformational asymmetry, and "ping-pong" kinetic properties of E1 and other thiamine-dependent enzymes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Binding Sites
  • Catalysis
  • Crystallography, X-Ray
  • Dihydrolipoyllysine-Residue Acetyltransferase
  • Geobacillus stearothermophilus / enzymology*
  • Hydrogen-Ion Concentration
  • Hydrophobic and Hydrophilic Interactions
  • Kinetics
  • Models, Molecular
  • Mutation
  • Phosphorylation
  • Protein Conformation
  • Protein Folding
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • Protons
  • Pyruvate Dehydrogenase (Lipoamide) / chemistry*
  • Pyruvate Dehydrogenase (Lipoamide) / genetics
  • Pyruvate Dehydrogenase (Lipoamide) / metabolism*
  • Pyruvate Dehydrogenase Complex / chemistry*
  • Pyruvate Dehydrogenase Complex / metabolism*
  • Pyruvic Acid / metabolism
  • Thiamine Pyrophosphate / metabolism*


  • Protein Subunits
  • Protons
  • Pyruvate Dehydrogenase Complex
  • Pyruvic Acid
  • Pyruvate Dehydrogenase (Lipoamide)
  • Dihydrolipoyllysine-Residue Acetyltransferase
  • Thiamine Pyrophosphate

Associated data

  • PDB/1W85
  • PDB/1W88