Mechanism of action and NAD+-binding mode revealed by the crystal structure of L-histidinol dehydrogenase

Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1859-64. doi: 10.1073/pnas.022476199. Epub 2002 Feb 12.


The histidine biosynthetic pathway is an ancient one found in bacteria, archaebacteria, fungi, and plants that converts 5-phosphoribosyl 1-pyrophosphate to l-histidine in 10 enzymatic reactions. This pathway provided a paradigm for the operon, transcriptional regulation of gene expression, and feedback inhibition of a pathway. l-histidinol dehydrogenase (HisD, EC ) catalyzes the last two steps in the biosynthesis of l-histidine: sequential NAD-dependent oxidations of l-histidinol to l-histidinaldehyde and then to l-histidine. HisD functions as a homodimer and requires the presence of one Zn(2+) cation per monomer. We have determined the three-dimensional structure of Escherichia coli HisD in the apo state as well as complexes with substrate, Zn(2+), and NAD(+) (best resolution is 1.7 A). Each monomer is made of four domains, whereas the intertwined dimer possibly results from domain swapping. Two domains display a very similar incomplete Rossmann fold that suggests an ancient event of gene duplication. Residues from both monomers form the active site. Zn(2+) plays a crucial role in substrate binding but is not directly involved in catalysis. The active site residue His-327 participates in acid-base catalysis, whereas Glu-326 activates a water molecule. NAD(+) binds weakly to one of the Rossmann fold domains in a manner different from that previously observed for other proteins having a Rossmann fold.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Oxidoreductases / chemistry*
  • Amino Acid Sequence
  • Binding Sites
  • Catalysis
  • Cloning, Molecular
  • Dimerization
  • Escherichia coli / enzymology
  • Histidine / chemistry
  • Models, Chemical
  • Models, Molecular
  • Molecular Sequence Data
  • NAD / metabolism*
  • Protein Binding
  • Protein Folding
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • X-Ray Diffraction
  • Zinc / chemistry


  • NAD
  • Histidine
  • Alcohol Oxidoreductases
  • histidinol dehydrogenase
  • Zinc

Associated data

  • PDB/1K75
  • PDB/1KAE
  • PDB/1KAH
  • PDB/1KAR