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Information on EC 1.1.1.23 - histidinol dehydrogenase and Organism(s) Escherichia coli and UniProt Accession P06988
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1.1.1.23 histidinol dehydrogenaseIUBMB Comments
Also oxidizes L-histidinal. The Neurospora enzyme also catalyses the reactions of EC 3.5.4.19 (phosphoribosyl-AMP cyclohydrolase) and EC 3.6.1.31 (phosphoribosyl-ATP diphosphatase).
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The taxonomic range for the selected organisms is: Escherichia coli
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
hdh, histidinol dehydrogenase, his4 protein, l-histidinol dehydrogenase, bshdh, l-histidinol:nad+ oxidoreductase, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
HDH
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L-histidinol dehydrogenase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
L-histidinol + 2 NAD+ + H2O = L-histidine + 2 NADH + 3 H+
reaction mechanism, amino acid residues Glu326 and His327 are involved in catalysis
L-histidinol + 2 NAD+ + H2O = L-histidine + 2 NADH + 3 H+
the enzyme catalyzes the sequential NAD-dependent oxidations of L-histidinol to L-histidinaldehyde and then to L-histidine using a bi-uni-uni-bi ping pong kinetic mechanism
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
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PATHWAY SOURCE
PATHWAYS
BRENDA
SYSTEMATIC NAME
IUBMB Comments
L-histidinol:NAD+ oxidoreductase
Also oxidizes L-histidinal. The Neurospora enzyme also catalyses the reactions of EC 3.5.4.19 (phosphoribosyl-AMP cyclohydrolase) and EC 3.6.1.31 (phosphoribosyl-ATP diphosphatase).
CAS REGISTRY NUMBER
COMMENTARY
9028-27-7
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
L-histidinol + 2 NAD+ + H2O
L-histidine + 2 NADH + 2 H+
part of L-histidine biosynthesis
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-
?
additional information
?
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active site binding structure for substrates L-histidinol, L-histamine, and L-histidine, NMR study
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?
L-histidinol + 2 NAD+ + H2O
L-histidine + 2 NADH + 3 H+
the enzyme is highly specific for histidinol and NAD+
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-
?
L-histidinal + NAD+ + H2O
L-histidine + NADH + H+
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reaction intermediate
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?
L-histidinal + NAD+ + H2O
L-histidine + NADH + H+
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reaction intermediate
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?
L-histidinal + NAD+ + H2O
L-histidine + NADH + H+
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reaction intermediate
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?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
L-histidinol + 2 NAD+ + H2O
L-histidine + 2 NADH + 2 H+
part of L-histidine biosynthesis
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-
?
L-histidinal + NAD+ + H2O
L-histidine + NADH + H+
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reaction intermediate
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?
L-histidinal + NAD+ + H2O
L-histidine + NADH + H+
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reaction intermediate
-
?
L-histidinal + NAD+ + H2O
L-histidine + NADH + H+
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reaction intermediate
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?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NAD+
the amine group is responsible of the substrate orientation by interacting with the Zn2+ while the overall stabilization of the cation changes between the unbound and bound forms
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mn2+
activates, to a higher degree than Zn2+, which stabilizes the enzyme in its catalytically active form
Zn2+
additional information
the presence of a divalent metal ion is essential for the enzymatic activity: replacement of the Zn2+ cation with Mg2+, Ni2+, Co2+ or Cu2+ causes a decrease of enzymatic activity, while replacement with Mn2+ or Cd2+ enhances the enzyme activity
Zn2+
metalloenzyme containing one Zn2+ cation in each subunit. Binding structure analysis
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
exploration of enzyme inhibitors for potential application as novel antimicrobial drugs
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
L-histidinol dehydrogenase (HDH, EC 1.1.1.23) is a 4-electron oxidoreductase involved in the last two steps of L-histidine biosynthesis
physiological function
role of the crucial enzyme in intracellular bacteria, overview. The enzyme acts as a HDH as a virulence factor in pathogenic bacteria with intramacrophagic development
additional information
two identical active sites, one in each subunit of the dimer. The dimer layout resulting in an active site displays a domain swapping between the monomers and allows a complete mapping of the Zn2+ and substrate binding by the involved residues
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
native HDH forms a dimer of identical or nearly identical subunits, it contains an incomplete Rossmann-fold in two domains of the protein. Crystal structure comparison with the enzyme from Brucella suis
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
15.4 mg/ml purified recombinant detagged enzyme alone or complexed with L-histidinol, L-histamine, or L-histidine or Zn2+ and NAD+, in 20 mM Tris-HCl, pH 7.5, 0.2 M NaCl, 5 mM DTT, 1 mM ligand, hanging drop vapour diffusion method, 18°C, 0.002 ml protein solution with 0.004 ml reservoir solution, containing 20% w/v PEG 3350, 7% v/v glycerol, 0.1 M imidazole-malic acid, pH 5.5, 0.2 M ammonium sulfate, 2 weeks, macroseeding for larger crystals, transfer to sodium acetate, pH 5.5, to eliminate the inhibiting imidazole, X-ray diffraction structure determination and analysis at 2.2 A resolution, modelling
crystal structure determination of HDH in its native state and with several substrates and Zn2+. the NAD+ molecule is crystallized with L-histidinol into the active site. In the apo structure, the Zn2+ coordination is tetrahedral, while it is octahedral in the inhibitor/enzyme complex
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
65
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almost no loss of activity after 5 min at pH 7.5, histidinol, 2 mM and MnCl2, 1 mM, protect enzyme from heat inactivation
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
55°C, 40% ammonium sulfate, Sephadex G-50, DEAE-cellulose, crystallization
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60°C, pH 5 treatment, ammonium sulfate precipitation, gel filtration, DEAE-cellulose, gel filtration
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene hisD, expression as glutathione S-transferase fusion protein with a thrombin cleavage site between tag and enzyme
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
histidinol dehydrogenase is a target for the development of antimicrobial agents, overview
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Andorn, N.; Aronovitch, J.
Purification and properties of histidinol dehydrogenase from Escherichia coli B
J. Gen. Microbiol.
128
579-584
1982
Escherichia coli
Bitar, K.G.; Firca, J.R.; Loper, J.C.
Histidinol dehydrogenase from salmonella typhimurium and escherichia coli. Purification, some characteristics and the amino acid sequence around a reactive thiol group
Biochim. Biophys. Acta
493
429-440
1977
Escherichia coli, Salmonella enterica subsp. enterica serovar Typhimurium
Adams, E.
The enzymatic synthesis of histidine from histidinol
J. Biol. Chem.
209
829-846
1954
Paenarthrobacter histidinolovorans, Escherichia coli
Barbosa, J.A.; Sivaraman, J.; Li, Y.; Larocque, R.; Matte, A.; Schrag, J.D.; Cygler, M.
Mechanism of action and NAD+-binding mode revealed by the crystal structure of L-histidinol dehydrogenase
Proc. Natl. Acad. Sci. USA
99
1859-1864
2002
Escherichia coli (P06988), Escherichia coli
Koehler, S.; Dessolin, J.; Winum, J.
Inhibitors of histidinol dehydrogenase
Top. Med. Chem.
22
35-46
2017
Brassica oleracea (P24226), Brucella sp., Brucella suis (Q8G2R2), Brucella suis 1330 (Q8G2R2), Burkholderia pseudomallei (Q63Q86), Burkholderia pseudomallei K96243 (Q63Q86), Escherichia coli (P06988), Geotrichum candidum (A0A0J9X7D2), Mycobacterium tuberculosis (P9WNW9), Mycobacterium tuberculosis H37Rv (P9WNW9), Salmonella enterica subsp. enterica serovar Typhimurium (P10370)
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