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Information on EC 1.13.11.5 - homogentisate 1,2-dioxygenase and Organism(s) Homo sapiens
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1.13.11.5 homogentisate 1,2-dioxygenaseIUBMB Comments
Requires Fe2+.
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Word Map
- 1.13.11.5
- alkaptonuria
-
ochronosis
- urine
- joint
- cartilage
- arthropathy
- sclera
- nitisinone
-
arthroplasty
-
discoloration
-
darken
- maleylacetoacetate
-
melanin-like
-
calculi
-
pyomelanin
-
ultra-rare
- 4-hydroxyphenylpyruvate
-
slovakia
- medicine
- ntbc
- diagnostics
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
homogentisate 1,2-dioxygenase, homogentisic acid oxidase, homogentisate dioxygenase, homogentisate 1,2 dioxygenase, elhdo, homogentisic acid 1,2-dioxygenase, homogentisate oxidase, homogentisate oxygenase, homogentisate phytyl-transferase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
HgD
HGO
homogentisate dioxygenase
homogentisate oxidase
-
-
-
-
homogentisate oxygenase
-
-
-
-
homogentisic acid oxidase
-
-
-
-
homogentisic acid oxygenase
-
-
-
-
homogentisic oxygenase
-
-
-
-
homogentisicase
-
-
-
-
HTO
-
-
-
-
HGO
-
-
-
-
homogentisate dioxygenase
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
-
-
SYSTEMATIC NAME
IUBMB Comments
homogentisate:oxygen 1,2-oxidoreductase (decyclizing)
Requires Fe2+.
CAS REGISTRY NUMBER
COMMENTARY
9029-49-6
-
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
3-chlorohomogentisate + O2
3-chloro-4-maleylacetoacetate
-
1% of activity with homogentisate
-
-
?
3-methylhomogentisate + O2
3-methyl-4-maleylacetoacetate
-
10% of activity with homogentisate
-
-
?
additional information
?
-
-
enzyme structure, conformation of the active site, enzyme contains a 280-residue N-terminal domain and a 140-residue C-terminal domain, associated as a hexamer arranged as a dimer of trimers
-
-
?
homogentisate + O2
4-maleylacetoacetate
-
utilizes a nonheme iron to incorporate both atoms of molecular oxygen into homogentisate, identical with 2,5-dihydroxyphenylacetate
-
?
homogentisate + O2
4-maleylacetoacetate
-
enzyme catalyzes an intermediate step in the catabolism of tyrosine and phenylalanine
-
-
?
homogentisate + O2
4-maleylacetoacetate
-
enzyme cleaves the aromatic ring during the metabolic degradation of phenylalanine and tyrosine
-
-
?
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
homogentisate + O2
4-maleylacetoacetate
-
enzyme catalyzes an intermediate step in the catabolism of tyrosine and phenylalanine
-
-
?
homogentisate + O2
4-maleylacetoacetate
-
enzyme cleaves the aromatic ring during the metabolic degradation of phenylalanine and tyrosine
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
Fe2+
-
contains a nonheme Fe2+ at the active site, that is coordinated near the interface between subunits in the HGO trimer by Glu-341, His-335 and His-371
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1,10-phenanthroline
-
inactivation in the absence of O2 due to formation of a white precipitate corresponding to apoprotein
3-chlorohomogentisate
-
inactivation in the presence of O2 due to formation of a white precipitate corresponding to apoprotein
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.0014
mutant enzyme I216T, pH and temperature not specified in the publication
0.0132
mutant enzyme W60G, pH and temperature not specified in the publication
0.023
mutant enzyme R225H, pH and temperature not specified in the publication
0.7
mutant enzyme S189I, pH and temperature not specified in the publication
19.275
mutant enzyme H80Q, pH and temperature not specified in the publication
20.932
wild type enzyme, pH and temperature not specified in the publication
4.708
mutant enzyme Y62C, pH and temperature not specified in the publication
5.972
mutant enzyme E42A, pH and temperature not specified in the publication
6.842
mutant enzyme A122D, pH and temperature not specified in the publication
7.715
mutant enzyme M368V, pH and temperature not specified in the publication
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
primary culture, alkaptonuria chondrocytes show a 10% increase of the enzyme expression compared to normal ones
additional information
enzyme expression analysis in human normal and alkaptonuria chondrocytes, synoviocytes, osteoblasts as well as in human osteosarcoma cells, overview
additional information
-
enzyme expression analysis in human normal and alkaptonuria chondrocytes, synoviocytes, osteoblasts as well as in human osteosarcoma cells, overview
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
-
the G161R natural mutation in the HGD gene occurs in a Hungarian population, originating from Slovakia, resists over 300 years, alkaptonuria phenotype overview
malfunction
physiological function
essential enzyme for the catabolism of phenylalanine and tyrosine
additional information
-
mutations in homogentisate 1,2-dioxygenase cause alkaptonuria and subsequent ochronosis, an uncommon cause of backache. The phenotype includes limited spine mobility and chronic disk degeneration, overview
malfunction
-
alkaptonuria is a rare autosomal recessive disease, associated with deficiency of homogentisate 1,2-dioxygenase activity in the liver. This leads to an accumulation of homogentisic acid and its oxidized derivatives in polymerized form in connective tissues, especially in joints. Homogentisic acid induces apoptosis in chondrocytes. N-acetylcysteine decreases apoptosis induced in chondrocytes by HGA, increases chondrocyte growth reduced by homogentisate, and partially restores proteoglycan release inhibited by homogentisate, the effect is improved by addition of ascorbic acid. Evaluation of antioxidant drugs for the treatment of ochronotic alkaptonuria, caused by homogentisate 1,2-dioxygenase activity mutation, in an in vitro human cell model, overview
malfunction
alkaptonuria results from defective homogentisate1,2-dioxygenase, causing degenerative arthropathy. The deposition of ochronotic pigment in joints is so far attributed to homogentisic acid produced by the liver, circulating in the blood and accumulating locally. Alkaptonuria osteoarticular cells produce the ochronotic pigment in loco and this may strongly contribute to induction of ochronotic arthropath
malfunction
enzyme mutations in the homogentisate 1,2 dioxygenase gene are responsible for alkaptonuria in patients among Jordanian population, genotyping, overview
malfunction
Alkaptonuria (AKU) is an ultra-rare disease caused by mutations in homogentisate 1,2-dioxygenase (HGD) enzyme, characterized by the loss of enzymatic activity and the accumulation of its substrate, homogentisic acid (HGA) in different tissues, leading to ochronosis and organ degeneration
malfunction
alkaptonuria is an autosomal recessive disorder, which is caused by a site-specific mutation(s) and thus, impairs the function of homogentisate-1, 2-dioxygenase
malfunction
alkaptonuria is an autosomal recessive disorder, which is caused by a site-specific mutations and thus, impairs the function of homogentisate-1,2-dioxygenase
malfunction
alkaptonuria is an inherited disease caused by homogentisate 1,2-dioxygenase deficiency
malfunction
alkaptonuria is an inherited disease that is caused by homogenticate accumulation. Deficiency or mutation in homogentisate 1,2-dioxygenase gene (chromosome 3q21-q23) lead to production of incorrectly folded or truncated enzyme
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). HGD_HUMAN
445
0
49964
Swiss-Prot
other Location (Reliability: 1)
B3KW64_HUMAN
304
0
34281
TrEMBL
other Location (Reliability: 1)
H7C576_HUMAN
145
0
16348
TrEMBL
other Location (Reliability: 2)
C9JTX9_HUMAN
142
0
16121
TrEMBL
other Location (Reliability: 5)
H7C5G7_HUMAN
98
0
11095
TrEMBL
other Location (Reliability: 2)
H7C4R8_HUMAN
88
0
9946
TrEMBL
other Location (Reliability: 2)
Q8WW71_HUMAN
329
0
37262
TrEMBL
other Location (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
450000 - 480000
-
sucrose density gradient centrifugation, can be degraded in two proteins of 200 and 230 kDa, probably due to inactivation by air
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hexamer
homohexamer
hexamer
-
hexamer arranged as a dimer of trimers, subunit structure, functional importance of the hexamer in vivo
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A122D
C1273A
naturally occuring mutation, the mutation is involved in alkaptonuria
E401Q
the missense variant E401Q is responsible for development of Alkaptonuria
E42A
the mutant shows strongly reduced specific activity compared to the wild type enzyme
G161R
-
naturally occuring mutation in the HGD gene, resulting in a specific genotype appearing in a Hungarian population, originating from Slovakia, with alkaptonuria, phenotype overview
H80Q
the mutant shows slightly reduced specific activity compared to the wild type enzyme
I216T
the mutant shows strongly reduced specific activity compared to the wild type enzyme
M368V
the mutant shows strongly reduced specific activity compared to the wild type enzyme
R225H
the mutant shows strongly reduced specific activity compared to the wild type enzyme
S189I
the mutant shows strongly reduced specific activity compared to the wild type enzyme
T1046G
naturally occuring mutation, the mutation is involved in alkaptonuria
T533G
naturally occuring mutation, the mutation is involved in alkaptonuria
T847C
naturally occuring mutation, the mutation is involved in alkaptonuria
V300G
W60G
Y62C
the mutant shows strongly reduced specific activity compared to the wild type enzyme
additional information
A122D
the mutant shows strongly reduced specific activity compared to the wild type enzyme
A122D
loss of structural and molecular dynamic properties of the enzyme, the mutation is potentially related with the severity of alkaptonuria
A122D
the mutation is potentially related with the severity of alkaptonuria
V300G
loss of structural and molecular dynamic properties of the enzyme, the mutation is potentially related with the severity of alkaptonuria
V300G
the mutation is potentially related with the severity of alkaptonuria
W60G
the mutant shows strongly reduced specific activity compared to the wild type enzyme
W60G
loss of structural and molecular dynamic properties of the enzyme, the mutation is potentially related with the severity of alkaptonuria
W60G
the mutation is potentially related with the severity of alkaptonuria
additional information
-
human gene for alkaptonuria is mapped to chromosome 3q2
additional information
alkaptonuric humans are deficient for homogentisate 1,2-dioxygenase and carry two copies of a loss-of-function allele of HGO gene
additional information
-
alkaptonuric humans are deficient for homogentisate 1,2-dioxygenase and carry two copies of a loss-of-function allele of HGO gene
additional information
-
20 missence mutations in HGO from alkaptonuria patients
additional information
the 551-552insG mutation is involved in alkaptonuria
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
DNA and ammino acid sequence determinaation and analysis, located on chromosome 3(q23-3q21), genotyping and identification of narurally occuring mutations involved in alkaptonuria, overview
HGO gene on chromosome 3 is cloned, completely sequenced and characterized, identification of its promoter region, transcriptional control of the gene
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
alkaptonuria: rare hereditary disorder of the phenylalanine catabolism, patients are deficient in homogentisate 1,2-dioxygenase and carry two copies of a loss-of-function allele of HGO gene, disease causes homogentisic aciduria, ochronosis and arthritis
medicine
-
HGO deficiency causes alkaptonuria, inherited as a recessive Mendelian trait, HGO inhibitors may be useful in the treatment of hereditary tyrosinemia type I, HT1
medicine
-
inactivation of enzyme in kidney and liver causes the basic defect of alkaptonuria
medicine
missense mutation in exon 13 (G360R) and exon 3 (K57N) affecting homogentisate 1,2-dioxygenase function by interfering with substrate traffic at active site causing alkaptonuria, a rare recessive phanylalanine/tyrosine metabolism disorder
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Granadino, B.; Beltran-Valero de Bernabe, D.; Fernandez-Canon, J.M.; Penalva, M.A.; Rodriguez de Cordoba, S.
The human homogentisate 1,2-dioxygenase (HGO) gene
Genomics
43
115-122
1997
Homo sapiens (Q93099), Homo sapiens
Hudecova, S.; Strakova, Z.; Krizanova, O.
Purification of the homogentisic acid oxidase from mammalian liver
Int. J. Biochem. Cell Biol.
27
1357-1363
1995
Bos taurus, Oryctolagus cuniculus, Homo sapiens, Mus musculus
Titus, G.P.; Mueller, H.A.; Burgner, J.; Rodriguez de Cordoba, S.; Penalva, M.A.; Timm, D.E.
Crystal structure of human homogentisate dioxygenase
Nat. Struct. Biol.
7
542-546
2000
Bos taurus, Homo sapiens, Mus musculus
Veldhuizen, E.J.; Vaillancourt, F.H.; Whiting, C.J.; Hsiao, M.M.; Gingras, G.; Xiao, Y.; Tanguay, R.M.; Boukouvalas, J.; Eltis, L.D.
Steady-state kinetics and inhibition of anaerobically purified human homogentisate 1,2-dioxygenase
Biochem. J.
386
305-314
2005
Homo sapiens
Borowski, T.; Georgiev, V.; Siegbahn, P.E.
Catalytic reaction mechanism of homogentisate dioxygenase: a hybrid DFT study
J. Am. Chem. Soc.
127
17303-17314
2005
Homo sapiens (Q93099), Homo sapiens
Grasko, J.M.; Hooper, A.J.; Brown, J.W.; McKnight, C.J.; Burnett, J.R.
A novel missense HGD gene mutation, K57N, in a patient with alkaptonuria
Clin. Chim. Acta
403
254-256
2009
Homo sapiens (Q93099)
Tinti, L.; Spreafico, A.; Braconi, D.; Millucci, L.; Bernardini, G.; Chellini, F.; Cavallo, G.; Selvi, E.; Galeazzi, M.; Marcolongo, R.; Gallagher, J.A.; Santucci, A.
Evaluation of antioxidant drugs for the treatment of ochronotic alkaptonuria in an in vitro human cell model
J. Cell. Physiol.
225
84-91
2010
Homo sapiens
Toth, K.; Kiss-Laaszlo, Z.; Lenart, E.; Juhasz, K.; Takacs, K.; Bender, T.; Szabo, J.
Familiar ochronotic arthropathy-caused by a gene mutation traced three hundred years
Joint Bone Spine
77
355-357
2010
Homo sapiens
Effelsberg, N.; Huegle, T.; Walker, U.
A metabolic cause of spinal deformity
Metab. Clin. Exp.
59
140-143
2010
Homo sapiens
Laschi, M.; Tinti, L.; Braconi, D.; Millucci, L.; Ghezzi, L.; Amato, L.; Selvi, E.; Spreafico, A.; Bernardini, G.; Santucci, A.
Homogentisate 1,2 dioxygenase is expressed in human osteoarticular cells: implications in alkaptonuria
J. Cell. Physiol.
227
3254-3257
2012
Homo sapiens (Q93099), Homo sapiens
Al-sbou, M.
Novel mutations in the homogentisate 1,2 dioxygenase gene identified in Jordanian patients with alkaptonuria
Rheumatol. Int.
32
1741-1746
2012
Homo sapiens (Q93099), Homo sapiens
Bernini, A.; Galderisi, S.; Spiga, O.; Bernardini, G.; Niccolai, N.; Manetti, F.; Santucci, A.
Toward a generalized computational workflow for exploiting transient pockets as new targets for small molecule stabilizers Application to the homogentisate 1,2-dioxygenase mutants at the base of rare disease alkaptonuria
Comput. Biol. Chem.
70
133-141
2017
Homo sapiens (Q93099)
Bernardini, G.; Laschi, M.; Geminiani, M.; Braconi, D.; Vannuccini, E.; Lupetti, P.; Manetti, F.; Millucci, L.; Santucci, A.
Homogentisate 1,2 dioxygenase is expressed in brain implications in alkaptonuria
J. Inherit. Metab. Dis.
38
807-814
2015
Homo sapiens, Mus musculus
Zolfaghari, N.
Molecular docking analysis of nitisinone with homogentisate 1,2 dioxygenase
Bioinformation
13
136-139
2017
Homo sapiens (Q93099)
Bernini, A.; Galderisi, S.; Spiga, O.; Amarabom, C.O.; Santucci, A.
Transient pockets as mediators of gas molecules routes inside proteins The case study of dioxygen pathway in homogentisate 1,2-dioxygenase and its implication in Alkaptonuria development
Comput. Biol. Chem.
88
107356
2020
Homo sapiens (Q93099)
Hughes, J.H.; Liu, K.; Plagge, A.; Wilson, P.J.M.; Sutherland, H.; Norman, B.P.; Hughes, A.T.; Keenan, C.M.; Milan, A.M.; Sakai, T.; Ranganath, L.R.; Gallagher, J.A.; Bou-Gharios, G.
Conditional targeting in mice reveals that hepatic homogentisate 1,2-dioxygenase activity is essential in reducing circulating homogentisic acid and for effective therapy in the genetic disease alkaptonuria
Hum. Mol. Genet.
28
3928-3939
2019
Homo sapiens (Q93099)
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