Sandbox Reserved 772

This Sandbox is Reserved from Sep 25, 2013, through Mar 31, 2014 for use in the course "BCH455/555 Proteins and Molecular Mechanisms" taught by Michael B. Goshe at the North Carolina State University. This reservation includes Sandbox Reserved 299, Sandbox Reserved 300 and Sandbox Reserved 760 through Sandbox Reserved 779.

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spinqualitylabelsall models Crystal structure of L-histidinol dehydrogenase with a functional homodimer in the asymmetric unit. Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Histidinol DehydrogenaseHistidinol Dehydrogenase

Histidinol dehydrogenase (HDH) is an enzyme that catalyzes the last step in the histidine biosynthetic pathway, which converts L-histidinol to L-histidine with a L-histidinaldehyde intermediate. This primordial pathway was found in bacteria, archaebacteria, fungi, and plants. HDH has been one of the most studied enzyme biochemically and genetically throughout time. HDH is encoded by the structural gene hisD.

General InformationGeneral Information

Gene Name: hisD

Organism: Escherichia coli (strain K12)

Classification: Oxidoreductase

Length: 434 Residues

Molecular Weight: 46107.65 Da

Isoelectric Point: 5.06

Chains: A, B

Ligands: glycerol (GOL), selenomethionine (MSE), sulfate ion (SO4)

StructureStructure

The overall structure is 48% helical (20 helices; 211 residues) and 16% beta sheet (15 strands; 73 residues). HisD is a monomer, but it functions as a homodimer. The presence of Zn2+ cation is required per monomer. Each hisD monomer is made of four domains,two larger domains (globule) and two smaller domains (extending tail), and the intertwined dimer was thought to result from domain swapping. The two domains presents a similar incomplete Rossmann fold, which suggests an ancient event of gene duplication. Residues from both monomers form the active site. The active site (residue His-327) participates in acid-base catalysis

Related Structures: 1KAE and 1KAR

Sequence of HDH

Enzymatic MechanismEnzymatic Mechanism

This bifunctional enzyme converts L-histidinol to L-histidine through a L-histidinaldehyde intermediate. His-327 is the active site and Glu-326 activates water molecule

The reaction above is catalyzed by HisD. The structure allows thebidentification of residues Glu-326 as being base B2 and His-327 as B1, B3, and B4. Glu-326 activates the water molecule that attacks the reactive carbon in step 2 of the reaction mechanism.

Implications or Possible ApplicationsImplications or Possible Applications

Brucellosis, commonly known as Maltafever, is the most widespread bacterial zoonosis worldwide. Its causative agent, Brucella spp., is a facultative intracellular pathogen developed inside the host’s macrophages.

The absence of a vaccine for humans and the appearing resistance of Brucella spp. to anti-biotic chemotherapy points to the necessity to develop new therapeutic strategies to eradicate this reemerging pathogen. The virulome analysis of Brucella suis shows that genes involved in the biosynthesis of amino acids are essential for the virulence of the bacteria.

Inhibition of its enzymatic activity with specific inhibitors will prevent intramacrophagic multiplication of Brucella. Histidinol dehydrogenase being exclusively necessary for the growth of the bacteria inside the macrophage of the host, and having no counterpart in mammalians, it constitutes a therapeutic target for the development of an anti-infectious treatment against intracellular pathogens.