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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Histidinol DehydrogenaseHistidinol Dehydrogenase

Histidinol dehydrogenase (HDH) is coded by the structural gene hisD. Histidinol dehydrogenase catalyzes the last step in the histidine biosynthetic pathway. This pathway was found in bacteria, archaebacteria, fungi, and plants. The pathway involves the conversion of L-histidinol to L-histidine with a L-histidinaldehyde intermediate

General InformationGeneral Information

Gene Name: hisD

Organism: Escherichia coli (strain K12)

Classification: Oxidoreductase

Length: 434 Amino Acids

Chains: A, B

Molecular Weight: 46107.65 Da

Isoelectric Point: 5.06

StructureStructure

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), 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. The active site, residue His-327, participates in acid-base catalysis

For the overall structure, it is 48% helical (20 helices; 211 residues) and 16% beta sheet (15 strands; 73 residues).

Related Structures: 1KAE and 1KAR

Enzymatic MechanismEnzymatic Mechanism

This bifunctional enzyme converts L-histidinol to L-histidine through a L-histidinaldehyde intermediate.

Implications or Possible ApplicationsImplications or Possible Applications

Brucellosis, most 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.

Pathogenesis is linked to this intramacrophagic replication. Due to its intracellular localization, eradication of Brucella spp. with standard chemotherapy strategies such as antibiotic treatment is delicate.

Moreover, clinical isolates show that drug-resistant Brucella strains are developing. 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 has shown that among others, genes involved in the biosynthesis of amino acids are essential for the virulence of the bacteria.

This new approach consists in targeting a virulence factor of this pathogen, the histidinol dehydrogenase (HDH, EC. 1.1.23). 5–7

This metalloenzyme is involved in the final two steps of the biosynthesis of histidine where it catalyses the NAD dependent oxidation of histidinol to histidine via histidinaldehyde.

Inhibition of its enzymatic activity with specific inhibitors will prevent intramacrophagic multiplication of Brucella. HDH being essential exclusively 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.