Information on EC 3.7.1.2 - fumarylacetoacetase

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria

EC NUMBER
COMMENTARY hide
3.7.1.2
-
RECOMMENDED NAME
GeneOntology No.
fumarylacetoacetase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
4-fumarylacetoacetate + H2O = acetoacetate + fumarate
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C-C-bond cleavage
hydrolysis of C-C bond
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
L-tyrosine degradation I
-
-
Metabolic pathways
-
-
Microbial metabolism in diverse environments
-
-
Styrene degradation
-
-
Tyrosine metabolism
-
-
tyrosine metabolism
-
-
SYSTEMATIC NAME
IUBMB Comments
4-fumarylacetoacetate fumarylhydrolase
Also acts on other 3,5- and 2,4-dioxo acids.
CAS REGISTRY NUMBER
COMMENTARY hide
9032-59-1
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
an Arabidopsis thaliana short-day sensitive cell death1 (sscd1) mutant displays a spontaneous cell death phenotype under short-day conditions, disruption of FAH leads to cell death, phenotype overview. The spontaneous cell death phenotype of the sscd1 mutant is completely eliminated by further knockout of the gene encoding the putative homogentisate dioxygenase, which catalyzes homogentisate into maleylacetoacetate (the antepenultimate step) in the Tyr degradation pathway. Treatment of Arabidopsis wild-type seedlings with succinylacetone, an abnormal metabolite caused by loss of FAH in the Tyr degradation pathway, mimicks the sscd1 cell death phenotype
metabolism
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
2,4-diketo-4-(4-methylphenyl) butyrate + H2O
pyruvate + (4-methylphenyl)acetate
show the reaction diagram
-
-
-
?
2,4-diketo-4-phenyl butyrate + H2O
pyruvate + phenylacetate
show the reaction diagram
-
-
-
?
2,4-diketo-5,5-dimethyl hexanoate + H2O
pyruvate + 2,2-dimethylpropanoate
show the reaction diagram
-
-
-
?
2,4-diketo-5-methyl heptanoate + H2O
pyruvate + 2-methylbutanoate
show the reaction diagram
-
-
-
?
2,4-diketo-5-methyl hexanoate + H2O
pyruvate + isobutanoate
show the reaction diagram
-
-
-
?
2,4-diketocaprate + H2O
pyruvate + heptanoate
show the reaction diagram
-
-
-
?
2,4-diketoheptanoate + H2O
pyruvate + butanoate
show the reaction diagram
-
-
-
?
2,4-diketohexanoate + H2O
pyruvate + propanoate
show the reaction diagram
2,4-diketononanoate + H2O
pyruvate + hexanoate
show the reaction diagram
-
-
-
?
2,4-diketooctanoate + H2O
pyruvate + pentanoate
show the reaction diagram
-
-
-
?
2,4-diketoundecanoate + H2O
pyruvate + octanoate
show the reaction diagram
-
-
-
?
2,4-diketovalerate + H2O
pyruvate + acetate
show the reaction diagram
-
-
-
?
3,5-dioxohexanoate + H2O
?
show the reaction diagram
-
-
-
?
3-benzoylpropionate + H2O
benzoate + propionate
show the reaction diagram
-
-
-
?
3-phenylpropionopyruvate + H2O
?
show the reaction diagram
-
-
-
?
4-ethyl oxaloacetate + H2O
?
show the reaction diagram
-
-
-
?
4-fumarylacetoacetate + H2O
acetoacetate + fumarate
show the reaction diagram
4-ketopimelate + H2O
succinate + propanoate
show the reaction diagram
-
-
-
?
5-phenyl-3,5-dioxopentanoate + H2O
?
show the reaction diagram
-
-
-
?
6,6-dimethyl-3,5-dioxoheptanoate + H2O
?
show the reaction diagram
-
-
-
?
acetoacetate + H2O
acetate
show the reaction diagram
-
-
-
?
acetopyruvate + H2O
?
show the reaction diagram
-
-
-
?
acetopyruvic acid + H2O
acetic acid + pyruvic acid
show the reaction diagram
-
-
-
?
acetylpyruvate + H2O
?
show the reaction diagram
-
-
-
-
?
alpha-ketobutyrate + H2O
?
show the reaction diagram
-
-
-
?
alpha-ketoglutarate + H2O
?
show the reaction diagram
-
-
-
?
benzoylpyruvate + H2O
pyruvate + benzoate
show the reaction diagram
-
-
-
?
butyropyruvate + H2O
?
show the reaction diagram
-
-
-
?
dihydroxytartrate + H2O
?
show the reaction diagram
-
-
-
?
maleylacetoacetate + H2O
acetoacetate + maleate
show the reaction diagram
-
-
-
-
?
oxaloacetate + H2O
?
show the reaction diagram
-
-
-
-
?
pivalopyruvate + H2O
?
show the reaction diagram
-
-
-
?
propionopyruvate + H2O
?
show the reaction diagram
pyruvate + H2O
?
show the reaction diagram
-
-
-
?
succinylacetoacetate + H2O
?
show the reaction diagram
-
-
-
?
triacetic acid + H2O
acetoacetic acid + acetic acid
show the reaction diagram
-
-
-
?
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
4-fumarylacetoacetate + H2O
acetoacetate + fumarate
show the reaction diagram
pyruvate + H2O
?
show the reaction diagram
-
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Cu2+
-
-
additional information
-
metal ligand binding distance analysis from crystal structure
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
3-benzoylpropionate
-
1 mM, 40% inhibition
3-[(3-carboxy-2-oxopropyl)hydroxyphosphinyl]acrylate
4-(hydroxymethylphosphinoyl)-3-oxo-butanoic acid
4-ethyl oxaloacetate
-
1 mM, 30% inhibition
4-ketopimelate
-
1 mM, 10% inhibition
4-[(2-carboxyethyl)-hydroxyphosphinyl]-3-oxobutyrate
5,5'-dithiobis(2-nitrobenzoic acid)
acetoacetate
-
1 mM, 30% inhibition
alpha-Ketobutyrate
-
1 mM, 50% inhibition
alpha-ketoglutarate
-
1 mM, 50% inhibition
Benzoylacetone
-
9 mM
Br-
-
50 mM for 50% inhibition
citrate
-
9 mM
Cl-
-
140 mM for 50% inhibition
ClO4-
-
6 mM for 50% inhibition
DFP
-
1 mM
Dihydroxytartrate
-
1 mM, 100% inhibition
F-
-
1.2 mM for 50% inhibition
Fe3+
-
inactivation by precipitating the proteins
HCO3-
-
170 mM for 50% inhibition
La3+
-
inactivation by precipitating the proteins
malonate
-
9 mM
N-ethylmaleimide
-
1 mM
NO3-
-
12 mM for 50% inhibition
oxalate
-
9 mM
oxaloacetate
-
1 mM, 90% inhibition
p-hydroxymercuribenzoate
pyruvate
-
-
SCN-
-
4.2 mM for 50% inhibition
succinylacetone
treatment of wild-type seedlings with succinylacetone mimicks the sscd1 phenotypes: the treated wild-type seedlings exhibit wilted leaves and slow-growth symptoms under long-day, these symptoms are more severe under short-day. The sscd1 mutant is more sensitive to succinylacetone than the wild type under long-day
trichloroacetate
-
1.2 mM for 50% inhibition
Trinitrobenzenesulfonic acid
-
1 mM
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.27
3,5-hexanedioate
-
-
-
0.22
3-phenylpropionopyruvate
-
-
0.0014
4-Fumarylacetoacetate
pH 7.3, 25C
0.89
5-phenyl-3,5-pentanedioate
-
-
-
0.14
6,6-dimethyl-3,5-heptanedioate
-
-
-
0.47
Acetopyruvate
-
-
0.12
benzoylpyruvate
-
-
0.31
butyropyruvate
-
-
0.021 - 1.2
Fumarylacetoacetate
0.64
pivalopyruvate
-
-
0.47 - 6
propionopyruvate
-
1.38
triacetic acid
-
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.000012
3-[(3-carboxy-2-oxopropyl)hydroxyphosphinyl]acrylate
-
-
0.085
4-(hydroxymethylphosphinoyl)-3-oxo-butanoic acid
-
37C, recombinant enzyme
0.000041
4-[(2-carboxyethyl)-hydroxyphosphinyl]-3-oxobutyrate
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.0004 - 0.032
-
liver, dependent on patients
0.018
-
kidney
0.025
-
kidney, 2,4-diketo-6-methyl heptanoate
0.026
-
kidney
0.036
-
kidney, 2,4-diketooctanoate
0.048
-
liver, 2,4-diketo-6-methyl heptanoate
0.0523
-
kidney, 2,4-diketoheptanoate
0.0547
-
kidney
0.055
-
liver
0.0575
-
kidney
0.061
-
kidney, 2,4-diketo-5,5-dimethyl hexanoate
0.0688
-
liver
0.07
-
liver, 2,4-diketooctanoate
0.0803
-
liver
0.0885
-
kidney, 2,4-diketononanoate
0.0923
-
liver, 2,4-diketoheptanoate
0.103
-
liver, 2,4-diketo-5,5-dimethyl hexanoate
0.111
-
liver, 2,4-diketoundecanoate
0.127
-
kidney, 2,4-diketovalerate
0.148
-
kidney, 2,4-diketo-5-methyl hexanoate
0.16
-
kidney, 2,4-diketocaprate
0.168
-
liver, 2,4-diketononanoate
0.245
-
kidney, 2,4-diketohexanoate
0.248
-
liver, 2,4-diketo-5-methyl hexanoate
0.25
-
liver, 2,4-diketovalerate
0.337
-
liver, 2,4-diketocaprate
0.35
-
-
0.395
-
liver, 2,4-diketohexanoate
0.495
-
kidney, 2,4-diketoundecanoate
1.77
purified recombinant enzyme, substrate fumarylacetoacetate, pH 7.3, 25C
36.3
-
-
1558
-
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.5
-
in maleate buffer
7.5 - 7.8
-
2,4-diketohexanoate
8
-
in phosphate and borate buffer
8 - 8.5
-
2,4-diketocaprate
8 - 8.6
-
2,4-diketononanoate
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6 - 8.5
-
-
6.25 - 8.5
-
-
6.8 - 7.6
-
-
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.9 - 6.1
isoelectric focusing
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
29400
-
determined by SDS-PAGE
33000
2 * 33000, SDS-PAGE
40000
-
2 * 40000, SDS-PAGE
41000
-
2 * 41000, SDS-PAGE
65000
-
SDS-PAGE
66000
about, native PAGE
80000
-
SDS-PAGE
83000
-
gel filtration
86000
-
gel filtration
87000
-
gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
homodimer
monomer or dimer
-
gel filtration analysis gives an estimated molecular mass of 65000 Da which is an equivalent to 1.4 monomers
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
a high-resolution crystal structure of the FAH-CEHPOBA complex is soved at 1.35 A
-
inhibitor complexed enzyme, 3 mg/ml purified hanging drop vapor diffusion method, room temperature, in a 2:1 ratio with precipitant solution, containing 17-18% PEG 8000, 0.03-0.15 nickel acetate, no to 0.24 M sodium acetate, 0.1 M sodium cacodylate, pH 6.5, soaking in inhibitor 4-(hydroxymethylphosphinoyl)-3-oxo-butanoic acid solution for 16 h prior to data collection via X-ray diffraction, structure determination and analysis at 1.3 A resolution
-
a recombinant form of the fumarylacetoacetase family member TTHA0809 from Thermus thermophilus HB8 is crystallized, diffraction data are collected at 2.2 A
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-70C, phosphate buffer, pH 7.2, several months
-
-70C, several years
-
4C, 1 month
-
frozen, 3 months
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
nickel-chelate affinity chromatography
-
recombinant enzyme 5.0fold from Escherichia coli strain BL21(DE3) by ammonium sulfate fractionation and anion exchange chromatography
recombinant His-tagged enzyme
-
recombinant His-tagged enzyme, fusion protein is cleaved from the fusion tag by bovine thrombin
-
using a HiPrep 26/10 desalting column, a Super Q Toyopearl 650M column, a Resource Q column, a Bio-Scale CHT-10-I column, and a HiLoad 16/60 Superdex 200 pg column
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
cloning of FAH genomic DNA and cDNA by degenerate PCR and RACE method, DNA and amino acid sequence determination and analysis, sequence comparisons, recombinant expression in Escherichia coli strain BL21(DE3) from pET28a-FAH
expressed in Escherichia coli
-
expression as glutathione S-transferase fusion protein
-
expression in BMT-10 cells
-
expression in CV-1 transfected cells
-
expression of C-terminally His-tagged enzyme in a bacterial expression system
-
for expression in Escherichia coli
generation of a Fah-knockout mutant as a model of hereditary tyrosinemia type I. Transplantation of wild-type bone marrow cells from fully allogeneic BALB/c donors into Fah-knockout mutant after lethal total body irradiation results in healthy recipients without pharmacological support
-
into the vector pET11a for expression in Escherichia coli BL21DE3 cells
-
proteome analysis. FAH protein level is down-regulated in the Fe2+ adequate fed TNF-deltaARE mutant and up-regulated in the Fe2+ low fed TNF-deltaARE mutant compared to wild-type
-
SSCD1 gene, DNA and amino acid sequence determination and analysis, map-based cloning
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A134D
-
mutant with decrased enzyme activity
F62C
-
mutant with decrased enzyme activity
A134D
-
-
C193R
-
mutant may affect the active-site geometry
D233V
-
mutant
G158D
-
mutant may affect the active site by perturbing the FAH quarternary structure; mutant may affect the active-site geometry
G207D
-
mutant may affect the active-site geometry
G369V
-
mutant may affect the active-site geometry
N16I
-
mutant may disrupt activity by causing misfolding
P249T
-
mutant may affect the active-site geometry
P261L
-
mutant may cause general structural effects or misfolding by disrupting the hydrophobic core, the native mainchain conformation and/or important electrostatic interactions
P342L
-
mutant may cause general structural effects or misfolding by disrupting the hydrophobic core, the native mainchain conformation and/or important electrostatic interactions
S405H
-
mutant may cause general structural effects or misfolding by disrupting the hydrophobic core, the native mainchain conformation and/or important electrostatic interactions
V166G
-
mutant may affect the active-site geometry
W234G
-
mutant may affect the active-site geometry
additional information
isolation and analysis of the sscd1-1 mutant. Generation of the sscd1 hgo double mutant through genetic crossing of sscd1-1 with hgo-1, an inactive homogentisate dioxygenase mutant, phenotypic analysis
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
biotechnology
-
participation in the synthesis of vitamin E and other tocopherols
degradation
medicine
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