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Enzyme Nomenclature
Information on EC 5.2.1.2 - maleylacetoacetate isomerase
for references in articles please use BRENDA:EC5.2.1.2
Word Map on EC 5.2.1.2
- 5.2.1.2
-
dichloroacetic
-
biotransformation
- fumarylacetoacetate
- glyoxylate
- acidosis
-
glutathione-dependent
- succinylacetone
-
dca-induced
-
chlorofluoroacetic
- homogentisate
- tyrosinemia
-
dihaloacetic
-
dehalogenation
- medicine
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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
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EC NUMBER 
COMMENTARY 
5.2.1.2
-
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RECOMMENDED NAME
GeneOntology No.
maleylacetoacetate isomerase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
4-Maleylacetoacetate = 4-fumarylacetoacetate
mechanism, preferred binding order is maleylacetone followed by glutathione
-
4-Maleylacetoacetate = 4-fumarylacetoacetate
ordered sequence of binding: maleylacetone first followed by glutathione
-
4-Maleylacetoacetate = 4-fumarylacetoacetate
tyrosine degradation leads to the formation of homogentisate, maleylacetoacetate isomerase, homogentisate dioxygenase and fumarylacetoacetate hydrolase are expressed in Arabidopsis thaliana to generate fumarate and acetoacetate
4-Maleylacetoacetate = 4-fumarylacetoacetate
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
cis-trans-isomerization
cis-trans-isomerization
-
-
double bond
-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
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SYSTEMATIC NAME
IUBMB Comments
4-maleylacetoacetate cis-trans-isomerase
Also acts on maleylpyruvate.
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CAS REGISTRY NUMBER
COMMENTARY
9023-75-0
-
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
-
human polymorphisms in the glutathione transferase zeta 1/maleylacetoacetate isomerase gene influence the toxicokinetics of dichloroacetate, GSTz1/MAAI haplotype significantly affects the kinetics and biotransformation of dichloroacetate. GSTz1/MAAI variants associated with the slowest rates of dichlorocacetate metabolism induce structural changes in the enzyme homodimer, predicting protein instability or abnormal protein-protein interactions. Enzyme inhibition also results in the accumulation of the potentially hepatotoxic tyrosine intermediates maleylacetoacetate and maleylacetone and of delta-aminolevulinate
metabolism
metabolism
-
catalyses a significant step in the catabolism of phenylalanine and tyrosine
metabolism
-
the bifunctional enzyme glutathione transferase zeta/maleylacetoacetate isomerase is the penultimate enzyme in the phenylalanine/tyrosine catabolic pathway
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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
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid + glutathione
2-(glutathion-S-yl)-3-(4-nitrophenyl)propanoic acid
Monomethyl 5-oxo-1(E),3(Z)-hexadien-1-ylphosphonate monoanion
Monomethyl 5-oxo-1(Z),3(E)-hexadien-1-ylphosphonate monoanion
-
cis-trans double isomerization
-
-
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid + glutathione
2-(glutathion-S-yl)-3-(4-nitrophenyl)propanoic acid
-
it is proposed that the charged side chain of Arg-175 forms a salt bridge with the carboxylate of the alpha-halo acid substrates
-
?
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid + glutathione
2-(glutathion-S-yl)-3-(4-nitrophenyl)propanoic acid
-
-
-
-
-
6-Oxo-2(E),4(Z)-heptanedienoic acid
6-Oxo-2(Z),4(E)-heptanedienoic acid
-
-
-
-
6-Oxo-2(E),4(Z)-heptanedienoic acid
6-Oxo-2(Z),4(E)-heptanedienoic acid
-
cis-trans double isomerization
-
-
6-Oxo-2(E),4(Z)-heptanedienoic acid
6-Oxo-2(Z),4(E)-heptanedienoic acid
-
r, reverse reaction is catalyzed in presence of GSH
-
-
6-Oxo-2(E),4(Z)-heptanedienoic acid
6-Oxo-2(Z),4(E)-heptanedienoic acid
-
cis-trans double isomerization
-
-
6-Oxo-2(E),4(Z)-heptanedienoic acid
6-Oxo-2(Z),4(E)-heptanedienoic acid
-
r, reverse reaction is catalyzed in presence of GSH
-
-
Maleylacetoacetate
?
human maleylacetoacetate isomerase deficiency presumably causes tyrosinemia that can be characterized by the absence of succinylacetone
-
-
-
Maleylacetoacetate
?
-
enzymatic isomerization of cis,cis-muconaldehydic acid to trans,trans-muconaldehydic acid followed by the oxidation is suggested to be the path to trans,trans-muconate
-
-
-
Maleylacetoacetate
?
-
one of the enzymes responsible for the oxidative metabolism of aromatic amino acids
-
-
-
Maleylpyruvate
Fumarylpyruvate
-
about 20fold higher activity than with maleylacetoacetate
-
-
additional information
?
-
-
enzyme deficiency would presumably cause tyrosinemia that would be characterized by the absence of succinylacetone
-
?
additional information
?
-
enzyme deficiency would presumably cause tyrosinemia that would be characterized by the absence of succinylacetone
-
?
additional information
?
-
-
key enzyme in the metabolic degradation of phenylalanine and tyrosine
-
?
additional information
?
-
-
the enzyme plays an important role in the metabolism of tyrosine
-
?
additional information
?
-
-
the bifunctional enzyme dehalogenates dichloroacetate to glyoxalate via its zeta-1 family glutathione transferase activity. Dichloroacetate is relevant to environmental science and allopathic medicine. The sensitivity to the inhibitor varies between enzyme haplotypes. Three nonsynonymous single-nucleotide polymorphisms of GSTz1/MAAI show different activity toward dichloroacetate and certain other xenobiotic haloacids
-
-
-
additional information
?
-
-
GSTzeta/MAAI is induced during the differentiation of 3T3-L1 fibroblasts into adipocytes. This process requires expression of C/EBPalpha as well as PPARgamma
-
-
-
additional information
?
-
-
the enzyme catalyzes the penultimate step in catabolic pathways for phenylalanine and tyrosine. BABL/c GSTZ1/MAAI-deficient mice show a number of significant abnormalities including altered organ sizes, an abnormal pattern of circulating leukocytes, and the consitutive induction of hepatic alpha, mu and pi class glutathione transferases
-
-
-
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NATURAL SUBSTRATES
NATURAL PRODUCTS
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
Maleylacetoacetate
?
O43708
human maleylacetoacetate isomerase deficiency presumably causes tyrosinemia that can be characterized by the absence of succinylacetone
-
-
-
Maleylacetoacetate
?
-
enzymatic isomerization of cis,cis-muconaldehydic acid to trans,trans-muconaldehydic acid followed by the oxidation is suggested to be the path to trans,trans-muconate
-
-
-
Maleylacetoacetate
?
-
one of the enzymes responsible for the oxidative metabolism of aromatic amino acids
-
-
-
additional information
?
-
-
enzyme deficiency would presumably cause tyrosinemia that would be characterized by the absence of succinylacetone
-
?
additional information
?
-
O43708
enzyme deficiency would presumably cause tyrosinemia that would be characterized by the absence of succinylacetone
-
?
additional information
?
-
-
key enzyme in the metabolic degradation of phenylalanine and tyrosine
-
?
additional information
?
-
-
the enzyme plays an important role in the metabolism of tyrosine
-
?
additional information
?
-
-
GSTzeta/MAAI is induced during the differentiation of 3T3-L1 fibroblasts into adipocytes. This process requires expression of C/EBPalpha as well as PPARgamma
-
-
-
additional information
?
-
-
the enzyme catalyzes the penultimate step in catabolic pathways for phenylalanine and tyrosine. BABL/c GSTZ1/MAAI-deficient mice show a number of significant abnormalities including altered organ sizes, an abnormal pattern of circulating leukocytes, and the consitutive induction of hepatic alpha, mu and pi class glutathione transferases
-
-
-
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Dichloroacetate
-
the sensitivity to the inhibitor varies between enzyme haplotypes. Three nonsynonymous single-nucleotide polymorphisms of GSTz1/MAAI show different activity toward dichloroacetate and certain other xenobiotic haloacids
maleylacetone
-
inhibits isomerization of 6-oxo-2(E),4(Z)-heptanedienoic acid into 6-oxo-2(Z),4(E)-heptanedienoic acid, and the reverse reaction
NaBH4
-
inhibition in absence of substrate, increases activity in presence of substrate and GSH
S-Glutathioyl-N-hexylmaleamate
-
competitive towards GSH, uncompetitive towards maleylacetone
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.023
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, mutant enzyme R175A
0.027
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, mutant enzyme R175K
0.029
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, enzyme hGSTZ1d-1d
0.044
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, enzyme hGSTZ1c-1c
0.096
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, enzyme hGSTZ1b-1b
0.128
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, enzyme hGSTZ1a-1a
0.319
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, mutant enzyme S15A
0.417
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, mutant enzyme C16A
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.19
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, mutant enzyme R175A
0.55
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, enzyme hGSTZ1d-1d
0.59
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, enzyme hGSTZ1c-1c
0.61
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, mutant enzyme R175K
0.82
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, enzyme hGSTZ1b-1b
1
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, mutant enzyme S15A
1.3
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, enzyme hGSTZ1a-1a
2.55
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, mutant enzyme C16A
6.08
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, enzyme hGSTZ1b-1b; pH 7.6, 25°C, enzyme hGSTZ1c-1c; pH 7.6, 25°C, mutant enzyme R175K
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
spectrophotometric assay with (+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
10.5 - 11
-
reaction with (+/-)-2-bromo-3-(4-nitrophenyl)propionic acid and glutathione
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
GSTzeta/MAAI is induced during the differentiation of 3T3-L1 fibroblasts into adipocytes. This process requires expression of C/EBPalpha as well as PPARgamma
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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PDB
SCOP
CATH
UNIPROT
ORGANISM
Anaeromyxobacter dehalogenans (strain 2CP-1 / ATCC BAA-258);
Q5ZT82
Legionella pneumophila subsp. pneumophila (strain Philadelphia 1 / ATCC 33152 / DSM 7513);
Mus musculus;
B8J605
Anaeromyxobacter dehalogenans (strain 2CP-1 / ATCC BAA-258);
B8J605
Anaeromyxobacter dehalogenans (strain 2CP-1 / ATCC BAA-258);
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
16000
16000
-
x * 16000, SDS-PAGE after heating the enzyme at 100°C for 10 min in a standard aqueous medium containing 1% SDS and 8M urea
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SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
-
x * 16000, SDS-PAGE after heating the enzyme at 100°C for 10 min in a standard aqueous medium containing 1% SDS and 8M urea; x * 35000, SDS-PAGE
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Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
expression in Escherichia coli, his-tagged protein is mainly insoluble
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C16A
-
the ratio of turnover number to KM-value for (+/-)-2-bromo-3-(4-nitrophenyl)propionic acid is 2.1fold decreased compared to the wild-type enzyme, the ratio of turnover number to KM-value for 4-maleylacetoacetate is 1.6fold increased compared to wild-type enzyme
R175A
-
the ratio of turnover number to KM-value for (+/-)-2-bromo-3-(4-nitrophenyl)propionic acid is 1.5fold decreased compared to the wild-type enzyme, the ratio of turnover number to KM-value for 4-maleylacetoacetate is 6.8fold decreased compared to wild-type enzyme
R175K
-
the ratio of turnover number to KM-value for (+/-)-2-bromo-3-(4-nitrophenyl)propionic acid is 1.8fold increased compared to the wild-type enzyme, the ratio of turnover number to KM-value for 4-maleylacetoacetate is 1.3fold increased compared to wild-type enzyme
S14A
-
mutant enzyme shows no activity with {(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid} or 4-maleylacetoacetate
S15A
-
the ratio of turnover number to KM-value for (+/-)-2-bromo-3-(4-nitrophenyl)propionic acid is 2.3fold decreased compared to the wild-type enzyme, the ratio of turnover number to KM-value for 4-maleylacetoacetate is 11.8fold decreased compared to wild-type enzyme
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
-
cis and/or trans isomers of 2,4-dioxohept-2-enoic acid might be diagnostic for human deficiency of maleylacetoacetate isomerase
additional information
-
knowledge of the GSTz1/MAAI haplotype can be used prospectively to identify individuals at potential risk of dichloroacetate’s adverse side effects from environmental or clinical exposure or who may exhibit aberrant amino acid metabolism in response to dietary protein
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LINKS TO OTHER DATABASES (specific for EC-Number 5.2.1.2)
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