PMID:11842181
| Citation |
Barbosa, JA, Sivaraman, J, Li, Y, Larocque, R, Matte, A, Schrag, JD and Cygler, M (2002) Mechanism of action and NAD+-binding mode revealed by the crystal structure of L-histidinol dehydrogenase. Proc. Natl. Acad. Sci. U.S.A. 99:1859-64 |
|---|---|
| Abstract |
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. |
| Links |
PubMed PMC122284 Online version:10.1073/pnas.022476199 |
| Keywords |
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 |
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