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Information on EC 5.2.1.2 - maleylacetoacetate isomerase and Organism(s) Homo sapiens
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EC Tree
5.2.1.2 maleylacetoacetate isomeraseIUBMB Comments
Also acts on maleylpyruvate.
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Word Map
- 5.2.1.2
- dichloroacetate
- fumarylacetoacetate
-
dca-induced
- succinylacetone
-
chlorofluoroacetic
- homogentisate
- tyrosinemia
- medicine
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
gstz1, gstz1-1, maleylacetoacetate isomerase, glutathione transferase zeta, gstz1/maai, gstzeta/maai, mac-ti, atmaai, maleylacetone isomerase, atgstz1, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Isomerase, maleylacetoacetate
-
-
-
-
MAAI
MAc-tI
-
-
-
-
Maleylacetoacetic isomerase
-
-
-
-
Maleylacetone cis-trans-isomerase
-
-
-
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Maleylacetone isomerase
-
-
-
-
additional information
glutathione transferase zeta 1, EC 2.5.1.18, bifunctional enzyme
MAAI
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
-
-
SYSTEMATIC NAME
IUBMB Comments
4-maleylacetoacetate cis-trans-isomerase
Also acts on maleylpyruvate.
CAS REGISTRY NUMBER
COMMENTARY
9023-75-0
-
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
-
it is proposed that the charged side chain of Arg-175 forms a salt bridge with the carboxylate of the alpha-halo acid substrates
-
?
Maleylacetoacetate
?
human maleylacetoacetate isomerase deficiency presumably causes tyrosinemia that can 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
?
-
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
?
-
-
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
-
-
?
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
Maleylacetoacetate
?
human maleylacetoacetate isomerase deficiency presumably causes tyrosinemia that can 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
?
-
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
?
-
-
key enzyme in the metabolic degradation of phenylalanine and tyrosine
-
?
additional information
?
-
-
the enzyme plays an important role in the metabolism of tyrosine
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(3Z)-1,3-butadiene-1,1,2,4-tetrol
competitive inhibitor identified by rational design, calculated to be no substrate and not inhibitory to CYP450 and nontoxic in AMES test
(Z)-3-[4-hydroxy-1-(hydroxymethyl)cyclohexyl]-2-propene-1,2-diol
competitive inhibitor identified by rational design, calculated to be no substrate and not inhibitory to CYP450 and nontoxic in AMES test
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
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
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
6.08
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, enzyme hGSTZ1c-1c
6.08
(+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
-
pH 7.6, 25°C, mutant enzyme R175K
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
spectrophotometric assay with (+/-)-2-bromo-3-(4-nitrophenyl)propionic acid
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
10.5 - 11
-
reaction with (+/-)-2-bromo-3-(4-nitrophenyl)propionic acid and glutathione
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
bifunctional enzyme, catalyzes reactions of EC 5.2.1.2 and glutathione-conjugating activity, EC 2.5.1.18
SwissProt
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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
-
the bifunctional enzyme glutathione transferase zeta/maleylacetoacetate isomerase is the penultimate enzyme in the phenylalanine/tyrosine catabolic pathway
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). MAAI_HUMAN
216
0
24212
Swiss-Prot
Mitochondrion (Reliability: 3)
B2RDN1_HUMAN
216
0
24126
TrEMBL
Mitochondrion (Reliability: 4)
A0A0C4DFM0_HUMAN
216
0
24114
TrEMBL
Mitochondrion (Reliability: 4)
G3V5T0_HUMAN
202
0
22610
TrEMBL
Mitochondrion (Reliability: 3)
G3V267_HUMAN
189
0
21075
TrEMBL
Mitochondrion (Reliability: 4)
G3V4T6_HUMAN
217
0
24232
TrEMBL
other Location (Reliability: 5)
PDB
SCOP
CATH
UNIPROT
ORGANISM
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
to 3.1 A resolution, space group P1, with unit-cell parameters a = 42.0, b= 49.6, c = 54.6 A, alpha = 82.9°, beta = 69.9°, gamma = 73.4°
PROTEIN VARIANTS
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
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
additional information
-
knowledge of the GSTz1/MAAI haplotype can be used prospectively to identify individuals at potential risk of dichloroacetates adverse side effects from environmental or clinical exposure or who may exhibit aberrant amino acid metabolism in response to dietary protein
medicine
cis and/or trans isomers of 2,4-dioxohept-2-enoic acid might be diagnostic for human deficiency of maleylacetoacetate isomerase
medicine
dichloroacetate, a degradation product of chloral hydrate, is further metabolized by glutathione transferase zeta 1, and inhibits its own metabolism through depletion/inactivation of GSTZ1/MAAI with repeated exposure, resulting in lower plasma clearance of the drug and the accumulation of the urinary biomarker maleylacetone. The amount of dichloroacetate produced from clinically relevant doses of chloral hydrate, although insufficient to alter dichloroacetate kinetics, is sufficient to inhibit MAAI and tyrosine catabolism
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Fernandez-Canon, J.M.; Penalva, M.A.
Characterization of a fungal maleylacetoacetate isomerase gene and identification of its human homologue
J. Biol. Chem.
273
329-337
1998
Aspergillus nidulans, Aspergillus nidulans (O43123), Homo sapiens, Homo sapiens (O43708)
Board, P.G.; Taylor, M.C.; Coggan, M.; Parker, M.W.; Lantum, H.B.; Anders, M.W.
Clarification of the role of key active site residues of glutathione transferase zeta/maleylacetoacetate isomerase by a new spectrophotometric technique
Biochem. J.
374
731-737
2003
Homo sapiens
Polekhina, G.; Board, P.G.; Blackburn, A.C.; Parker, M.W.
Crystal structure of maleylacetoacetate isomerase/glutathione transferase zeta reveals the molecular basis for its remarkable catalytic promiscuity
Biochemistry
40
1567-1576
2001
Homo sapiens (O43708), Homo sapiens
Shroads, A.L.; Langaee, T.; Coats, B.S.; Kurtz, T.L.; Bullock, J.R.; Weithorn, D.; Gong, Y.; Wagner, D.A.; Ostrov, D.A.; Johnson, J.A.; Stacpoole, P.W.
Human polymorphisms in the glutathione transferase zeta 1/maleylacetoacetate isomerase gene influence the toxicokinetics of dichloroacetate
J. Clin. Pharmacol.
52
837-849
2012
Homo sapiens
Boone, C.; Zhong, G.; Smeltz, M.; James, M.; McKenna, R.
Preliminary X-ray crystallographic analysis of glutathione transferase zeta 1 (GSTZ1a-1a)
Acta Crystallogr. Sect. F
70
187-189
2014
Homo sapiens (O43708)
Zolfaghari, N.
Competitive rational inhibitor design to 4-maleylaceto-acetate isomerase
Bioinformation
13
140-143
2017
Homo sapiens (O43708)
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