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Information on EC 3.4.19.9 - folate gamma-glutamyl hydrolase
for references in articles please use BRENDA:EC3.4.19.9
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EC Tree 3 Hydrolases
3.4 Acting on peptide bonds (peptidases)
3.4.19 Omega peptidases
3.4.19.9 folate gamma-glutamyl hydrolase
IUBMB Comments
The enzyme, which occurs only in animals and plants, can be either endo- and/or exopeptidase. It acts on tetrahydropteroyl polyglutamates and their modified forms, as well as the polyglutamates of the folate breakdown product N-(4-aminobenzoyl)-L-glutamate (pABA-Glu). The initial cleavage may release either monoglutamate or poly-γ-glutamate of two or more residues, depending on the specific enzyme. For example, GGH1 from the plant Arabidopsis thaliana cleaves pentaglutamates, mainly to di- and triglutamates, whereas GGH2 from the same organism yields mainly monoglutamates. The enzyme is lysosomal (and secreted) in animals and vacuolar in plants. In peptidase family C26.
The enzyme appears in viruses and cellular organisms
- 3.4.19.9
- polyglutamates
- methotrexate
-
polyglutamylation
- antifolate
- casei
- monoglutamates
- pteroylpolyglutamate
- sumo
-
monoglutamylated
- 5-methyltetrahydrofolate
-
deconjugation
-
trienzyme
- pentaglutamate
- rad6
- diglutamate
-
punicic
- medicine
- analysis
Reaction Schemes
show+
(n-1)
=
+
(n-1)
Synonyms
conjugase, gamma-glutamyl hydrolase, folate conjugase, folylpolyglutamate hydrolase, gamma-gh, leggh2, leggh3, zgammagh, leggh1, low gamma-glutamyl hydrolase, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
carboxypeptidase G
-
-
-
-
conjugase
EC 3.4.12.10
-
-
formerly
-
EC 3.4.22.12
-
-
formerly
-
FGPH
-
-
-
-
folate conjugase
-
-
-
-
folic acid conjugase
-
-
-
-
folylpolyglutamate hydrolase
-
-
-
-
gamma-Glu-X carboxypeptidase
-
-
-
-
gamma-glutamyl hydrolase
gammaGH
GGH
hydrolase, gamma-glutamyl
-
-
-
-
LeGGH3
expressed mainly in flower buds, the homodimer is catalytically inactive
lysosomal gamma-glutamyl carboxypeptidase
-
-
-
-
PghP
poly(gamma-glutamic acid) endohydrolase
-
-
-
-
poly(glutamic acid) hydrolase II
-
-
-
-
polyglutamate hydrolase
-
-
-
-
pteroyl-poly-gamma-glutamate hydrolase
-
-
-
-
pteroylpoly-gamma-glutamyl hydrolase
-
-
-
-
zgammaGH
conjugase
-
-
-
-
gamma-glutamyl hydrolase
-
-
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
tetrahydropteroyl-(gamma-glutamyl)n + (n-1) H2O = 5,6,7,8-tetrahydrofolate + (n-1) L-glutamate
tetrahydropteroyl-(gamma-glutamyl)n + (n-1) H2O = 5,6,7,8-tetrahydrofolate + (n-1) L-glutamate
-
-
-
-
tetrahydropteroyl-(gamma-glutamyl)n + (n-1) H2O = 5,6,7,8-tetrahydrofolate + (n-1) L-glutamate
Tyr36 is catalytically essential
-
tetrahydropteroyl-(gamma-glutamyl)n + (n-1) H2O = 5,6,7,8-tetrahydrofolate + (n-1) L-glutamate
Tyr36 is catalytically essential
tetrahydropteroyl-(gamma-glutamyl)n + (n-1) H2O = 5,6,7,8-tetrahydrofolate + (n-1) L-glutamate
catalytic mechanism, the enzyme releases mono- or di-glutamate
-
tetrahydropteroyl-(gamma-glutamyl)n + (n-1) H2O = 5,6,7,8-tetrahydrofolate + (n-1) L-glutamate
catalytic mechanism, the enzyme releases mono- or di-glutamate
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
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SYSTEMATIC NAME
IUBMB Comments
tetrahydropteroyl-poly-gamma-glutamyl gamma-glutamyl hydrolase
The enzyme, which occurs only in animals and plants, can be either endo- and/or exopeptidase. It acts on tetrahydropteroyl polyglutamates and their modified forms, as well as the polyglutamates of the folate breakdown product N-(4-aminobenzoyl)-L-glutamate (pABA-Glu). The initial cleavage may release either monoglutamate or poly-gamma-glutamate of two or more residues, depending on the specific enzyme. For example, GGH1 from the plant Arabidopsis thaliana cleaves pentaglutamates, mainly to di- and triglutamates, whereas GGH2 from the same organism yields mainly monoglutamates. The enzyme is lysosomal (and secreted) in animals and vacuolar in plants. In peptidase family C26.
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CAS REGISTRY NUMBER
COMMENTARY
9074-87-7
not distinguishable from EC 3.4.17.11 in Chemical Abstracts
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(4,4-difluoro)glutamyl-gamma-glutamate + H2O
(4,4-difluoro)glutamate + glutamate
-
Substrates: the fluorine substitution results in a significant decrease in rates of hydrolysis under steady-state conditions due primarily to a 15fold increase in Km compared to the unsubstituted substrate
Products: -
Products: -
?
(poly-gamma-glutamate)n + H2O
(poly-gamma-glutamate)n-1 + glutamate
-
Substrates: -
Products: -
Products: -
?
(poly-gamma-L-glutamate)n + H2O
oligo-gamma-L-glutamate
-
Substrates: -
Products: -
Products: -
?
2,4-diamino-10-methyl-pteroylglutamyl-gamma-glutamate + H2O
2,4-diamino-10-methyl-pteroate + glutamate + gamma-glutamylglutamate
-
Substrates: -
Products: bile enzyme at a ratio of 5:95 and plasma enzyme at a ratio of 23:77
Products: bile enzyme at a ratio of 5:95 and plasma enzyme at a ratio of 23:77
?
4-aminobenzoyl-(4,4-difluoro)glutamyl-gamma-glutamate + H2O
4-aminobenzoyl-(4,4-difluoro)glutamate + glutamate
-
Substrates: the fluorine substitution results in a significant decrease in rates of hydrolysis under steady-state conditions due primarily to a 15fold increase in Km compared to the unsubstituted substrate
Products: -
Products: -
?
4-aminobenzoyl-gamma-Glu + H2O
4-aminobenzoate + Glu
-
Substrates: -
Products: -
Products: -
?
4-aminobenzoyl-gamma-Glu-gamma-Glu-Tyr + H2O
?
-
Substrates: -
Products: -
Products: -
?
4-aminobenzoyl-penta-gamma-glutamate + H2O
4-aminobenzoylglutamate + tetra-gamma-glutamate
-
Substrates: -
Products: subsequently degraded to glutamic acid
Products: subsequently degraded to glutamic acid
?
4-aminobenzoyltriglutamate + H2O
?
-
Substrates: at 13% the rate of pteroyltriglutamate hydrolysis
Products: -
Products: -
?
4-hydroxy-2-nonenal-glutathione conjugate + H2O
4-hydroxy-2-nonenal-[Cys-Gly] conjugate + L-glutamate
-
Substrates: -
Products: -
Products: -
?
5,10-methenyltetrahydrofolate glutamate + H2O
5,10-methenyltetrahydrofolate + L-glutamate
Substrates: -
Products: -
Products: -
?
5,10-methenyltetrahydrofolate heptaglutamate + 7 H2O
5,10-methenyltetrahydrofolate + 7 L-glutamate
Substrates: -
Products: -
Products: -
?
5,10-methenyltetrahydrofolate hexaglutamate + 6 H2O
5,10-methenyltetrahydrofolate + 6 L-glutamate
Substrates: -
Products: -
Products: -
?
5-formyltetrahydrofolate glutamate + H2O
5-formyltetrahydrofolate + L-glutamate
Substrates: -
Products: -
Products: -
?
5-formyltetrahydrofolate heptaglutamate + 7 H2O
5-formyltetrahydrofolate + 7 L-glutamate
Substrates: -
Products: -
Products: -
?
5-formyltetrahydrofolate hexaglutamate + 6 H2O
5-formyltetrahydrofolate + 6 L-glutamate
Substrates: -
Products: -
Products: -
?
5-methyltetrahydrofolate glutamate + H2O
5-methyltetrahydrofolate + L-glutamate
Substrates: -
Products: -
Products: -
?
5-methyltetrahydrofolate heptaglutamate + 7 H2O
5-methyltetrahydrofolate + 7 L-glutamate
Substrates: -
Products: -
Products: -
?
5-methyltetrahydrofolate hexaglutamate + 6 H2O
5-methyltetrahydrofolate + 6 L-glutamate
Substrates: -
Products: -
Products: -
?
di-gamma-L-glutamate + H2O
L-glutamate
-
Substrates: -
Products: -
Products: -
?
folic acid pentaglutamate + H2O
?
Substrates: PteGlu5
Products: -
Products: -
?
methotrexate hexaglutamate + H2O
methotrexate pentaglutamate + methotrexate tetraglutamate + methotrexate triglutamate + methotrexate diglutamate + methotrexate monoglutamate
-
Substrates: -
Products: -
Products: -
?
methotrexate penta-gamma-glutamate + H2O
methotrexate-gamma-glutamate + tetra-gamma-glutamate
-
Substrates: -
Products: subsequently degraded to glutamic acid
Products: subsequently degraded to glutamic acid
?
methotrexate pentaglutamate + H2O
methotrexate glutamate + tetra-gamma-L-glutamate
Substrates: -
Products: -
Products: -
?
methotrexate pentaglutamate + H2O
methotrexate tetraglutamate + methotrexate triglutamate + methotrexate diglutamate + methotrexate monoglutamate + L-glutamate
-
Substrates: -
Products: -
Products: -
?
methotrexate triglutamate + H2O
methotrexate monoglutamate + methotrexate diglutamate + glutamate
-
Substrates: -
Products: -
Products: -
?
N5-methyltetrahydropteroyltetraglutamate + H2O
?
-
Substrates: cleaves the terminal gamma-glutamyl residues, finally releasing a monoglutamyl end-product
Products: -
Products: -
?
oligo-gamma-L-glutamate + H2O
L-glutamate
-
Substrates: -
Products: -
Products: -
?
p-aminobenzoylpentaglutamate + H2O
?
Substrates: pABAGlu5
Products: -
Products: -
?
pteroylglutamylhexaglutamate + H2O
short-chain pteroylglutamates
-
Substrates: -
Products: after 60 min incubation, pteroylglutamate is the major product after 120 min, with quantitative recovery of free glutamate, enzyme is an exopeptidase which progressively hydrolyzes glutamyl units from pteroylpolyglutamate, leaving pteroylmonoglutamate as the folate form available for intestinal transport
Products: after 60 min incubation, pteroylglutamate is the major product after 120 min, with quantitative recovery of free glutamate, enzyme is an exopeptidase which progressively hydrolyzes glutamyl units from pteroylpolyglutamate, leaving pteroylmonoglutamate as the folate form available for intestinal transport
?
tetra-gamma-L-glutamate + H2O
L-glutamate
-
Substrates: -
Products: -
Products: -
?
tri-gamma-L-glutamate + H2O
L-glutamate
-
Substrates: -
Products: -
Products: -
?
5-formyltetrahydrofolate triglutamate + H2O
?
Substrates: -
Products: -
Products: -
?
5-L-glutamyl-4-nitroanilide + H2O
L-glutamic acid + 4-nitroaniline
-
Substrates: -
Products: -
Products: -
?
5-L-glutamyl-4-nitroanilide + H2O
L-glutamic acid + 4-nitroaniline
-
Substrates: -
Products: -
Products: -
?
glutathione + H2O
?
-
Substrates: enzyme hydrolyses the physiological antioxidant glutathione, suggesting an involvement of the enzyme in the cellular defense mechanism against oxidative stress
Products: -
Products: -
?
glutathione + H2O
?
-
Substrates: enzyme hydrolyses the physiological antioxidant glutathione, suggesting an involvement of the enzyme in the cellular defense mechanism against oxidative stress
Products: -
Products: -
?
L-glutamic acid gamma-(4-nitroanilide) + H2O
L-glutamic acid + 4-nitroaniline
-
Substrates: -
Products: -
Products: -
?
L-glutamic acid gamma-(4-nitroanilide) + H2O
L-glutamic acid + 4-nitroaniline
-
Substrates: -
Products: -
Products: -
?
p-aminobenzoyl-penta-gamma-glutamate + H2O
?
Substrates: AtGGH1 cleaves pentaglutamates mainly to di- and triglutamates
Products: -
Products: -
?
p-aminobenzoyl-penta-gamma-glutamate + H2O
?
Substrates: AtGGH2 cleaves pentaglutamates mainly to monoglutamates
Products: -
Products: -
?
poly-Glu + H2O
?
-
Substrates: -
Products: Glu-Glu + oligomers of Glu
Products: Glu-Glu + oligomers of Glu
?
poly-Glu + H2O
?
-
Substrates: enzyme is specific for poly(gamma-glutamic) acid, but not for other gamma-glutamyl peptides or amides
Products: endo-type specificity, 38% of the original poly-Glu with an average MW of 500000 is converted to smaller peptides, and then depolymerized to a mixture of gamma-oligopeptides which consist of only L-glutamic acid, L-glutamic acid monomer is negligible in the reaction mixture, the remaining 62% of poly(gamma-glutamic acid) are resistant to the enzyme action
Products: endo-type specificity, 38% of the original poly-Glu with an average MW of 500000 is converted to smaller peptides, and then depolymerized to a mixture of gamma-oligopeptides which consist of only L-glutamic acid, L-glutamic acid monomer is negligible in the reaction mixture, the remaining 62% of poly(gamma-glutamic acid) are resistant to the enzyme action
?
poly-Glu + H2O
?
-
Substrates: enzyme is specific for poly(gamma-glutamic) acid, but not for other gamma-glutamyl peptides or amides
Products: endo-type specificity, 38% of the original poly-Glu with an average MW of 500000 is converted to smaller peptides, and then depolymerized to a mixture of gamma-oligopeptides which consist of only L-glutamic acid, L-glutamic acid monomer is negligible in the reaction mixture, the remaining 62% of poly(gamma-glutamic acid) are resistant to the enzyme action
Products: endo-type specificity, 38% of the original poly-Glu with an average MW of 500000 is converted to smaller peptides, and then depolymerized to a mixture of gamma-oligopeptides which consist of only L-glutamic acid, L-glutamic acid monomer is negligible in the reaction mixture, the remaining 62% of poly(gamma-glutamic acid) are resistant to the enzyme action
?
polyglutamyl-folate + H2O
monoglutamyl folate + glutamate
-
Substrates: -
Products: -
Products: -
?
polyglutamyl-folate + H2O
monoglutamyl folate + glutamate
-
Substrates: removal of the poly-gamma-glutamate chains
Products: -
Products: -
?
polyglutamyl-folate + H2O
monoglutamyl folate + glutamate
-
Substrates: -
Products: -
Products: -
?
polyglutamyl-folate + H2O
monoglutamyl folate + glutamate
Substrates: -
Products: -
Products: -
?
polyglutamyl-folate + H2O
monoglutamyl folate + glutamate
-
Substrates: -
Products: -
Products: -
?
polyglutamyl-folate + H2O
monoglutamyl folate + glutamate
-
Substrates: gamma-glutamyl hydrolase, not glutamate carboxypeptidase II, hydrolyzes dietary folate in rat small intestine
Products: -
Products: -
?
polyglutamyl-folate + H2O
monoglutamyl folate + glutamate
Substrates: removal of the poly-gamma-glutamate chains
Products: -
Products: -
?
polyglutamyl-folate + H2O
monoglutamyl folate + glutamate
-
Substrates: -
Products: -
Products: -
?
polyglutamylfolate + H2O
?
-
Substrates: bond cleavage occurs with equal facility at internal points of the peptide chain
Products: -
Products: -
?
polyglutamylfolate + H2O
?
-
Substrates: longer chain gamma-glutamyl peptides are preferentially attacked by the enzyme
Products: -
Products: -
?
polyglutamylfolate + H2O
?
-
Substrates: peptide bond cleavage occurs only at gamma-glutamyl bonds and the presence of a COOH-terminal gamma bond is essential for enzyme action
Products: -
Products: -
?
polyglutamylfolate + H2O
?
-
Substrates: the cleavage of diglutamyl peptides is extremely slow
Products: -
Products: -
?
polyglutamylfolate + H2O
?
-
Substrates: the cleavage of gamma bonds is independent of the NH2-terminal pteroyl moiety
Products: -
Products: -
?
polyglutamylfolate + H2O
?
-
Substrates: endopeptidase-like mode of action
Products: -
Products: -
?
polyglutamylfolate + H2O
?
-
Substrates: the ability of the gamma polyglutamate and the inability of the alpha polyglutamate to serve as substrate confirm the requirement for a terminal gamma peptide bond
Products: -
Products: -
?
polyglutamylfolate + H2O
?
-
Substrates: sequential hydrolysis of glutamates with the dissociation of substrate from enzymic surface following cleavage of each glutamate seems likely
Products: -
Products: -
?
polyglutamylfolate + H2O
?
-
Substrates: longer chain gamma-glutamyl peptides are preferentially attacked by the enzyme
Products: -
Products: -
?
polyglutamylfolate + H2O
?
-
Substrates: specificity towards analogs of pteroylglutamyl-gamma-glutamyl-gamma-glutamic acid
Products: -
Products: -
?
polyglutamylfolate + H2O
?
-
Substrates: analogs of the general structure pteroylglutamyl-gamma-glutamyl-gamma-R serve as substrates, low degree of specificity with regard to the nature of the-R group
Products: -
Products: -
?
polyglutamylfolate + H2O
?
-
Substrates: enzyme from mouse kidney shows mixed endo- and exopeptidase activity, the enzyme from all other normal tissues and tumor cells is consistent with endopeptidase activity
Products: -
Products: -
?
polyglutamylfolate + H2O
?
-
Substrates: endopeptidase-like mode of action
Products: -
Products: -
?
polyglutamylfolate + H2O
?
-
Substrates: endo/random hydrolysis of gamma-glutamyl peptide bonds of pteroylpolyglutamate substrates yielding folic acid as the terminal product
Products: -
Products: -
?
pteroyl-penta-gamma-glutamate + H2O
?
Substrates: AtGGH1 cleaves pentaglutamates mainly to di- and triglutamates
Products: -
Products: -
?
pteroyl-penta-gamma-glutamate + H2O
?
Substrates: AtGGH2 cleaves pentaglutamates mainly monoglutamates
Products: -
Products: -
?
pteroylheptaglutamate + H2O
?
-
Substrates: -
Products: pteroyldiglutamate + gamma-Glu5
Products: pteroyldiglutamate + gamma-Glu5
?
pteroylheptaglutamate + H2O
?
-
Substrates: -
Products: pteroylmonoglutamate + hexaglutamyl peptide
Products: pteroylmonoglutamate + hexaglutamyl peptide
?
pteroylpolyglutamate + H2O
?
-
Substrates: the enzyme is responsible for the intracellular cleavage of poly-gamma-glutamates
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: the enzyme is suggested to be involved in the destruction of microorganisms in granulocytes during phagocytosis
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: central enzyme in folyl and antifolylpoly-gamma-glutamate metabolism
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: key enzyme in the maintenance of cellular folylpolyglutamate concentration
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: central enzyme in folyl and antifolyl poly-gamma-glutamate metabolism
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: folate conjugase in the brush-border may accomplish the initial digestion of the dietary pteroylpolyglutamates
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: the enzyme progressively hydrolyzes glutamyl units from pteroylpolyglutamate, leaving pteroylmonoglutamate as the folate form available for intestinal transport
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: possible contribution of biliary enzyme to intestinal absorption of folate polyglutamates
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: pancreatic enzyme may act in vivo in folate digestion and absorption to initiate the deconjugation of dietary pteroylpolyglutamate prior to the action of jejunal brush-border enzyme
Products: -
Products: -
?
pteroyltriglutamate + H2O
pteroylglutamate + glutamate
-
Substrates: -
Products: -
Products: -
?
pteroyltriglutamate + H2O
pteroylglutamate + glutamate
-
Substrates: -
Products: -
Products: -
?
pteroyltriglutamate + H2O
pteroylglutamate + glutamate
-
Substrates: -
Products: + pteroyldiglutamate
Products: + pteroyldiglutamate
?
pteroyltriglutamate + H2O
pteroylglutamate + glutamate
-
Substrates: -
Products: -
Products: -
?
pteroyltriglutamate + H2O
pteroylglutamate + glutamate
-
Substrates: -
Products: -
Products: -
?
additional information
?
-
Substrates: isoform GGH2 alone is able to completely deconjugate folates using 50-100 microg/g of sample for 1 h at 37°C in all matrices tested. It removes the tails of folylpolyglutamates from tomato fruit, black bean and peanut seeds, and alfalfa sprouts extracts
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme specifically cleaves D- and L-polyglutamic acid, preferred to entirely of poly-D-glutamic acid, a component of the capsule produced by several strains of Bacillus subtilis, the enzyme has minimal activity in degrading Bacillus anthracis and to remove the capsule from the surface of bacilli, the poly-gamma-D-glutamic acid capsule, no effect on RAW264.7 murine macrophage phagocytosis, and only minimal enhancement of human host neutrophil killing
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme hydrolyzes synthetically hydrolyzed oligo-gamma-L-glutamates, but not oligo-gamma-D-glutamates, and degrades polyglutamic acid to a hydrolyzed product of about 20 kDa with a ratio of D- and L-glutamic acids of 70:30, thus the enzyme cleaves the bond between two L-glutamic acid residues, overview
Products: -
Products: -
?
additional information
?
-
Substrates: hydrolysis of the gamma-glutamate bond, resulting in folate-mono-Glu
Products: -
Products: -
?
additional information
?
-
-
Substrates: hydrolysis of the gamma-glutamate bond, resulting in folate-mono-Glu
Products: -
Products: -
?
additional information
?
-
Substrates: hydrolysis of the gamma-glutamate bond, resulting in folate-mono-Glu
Products: -
Products: -
?
additional information
?
-
-
Substrates: no hydrolysis of alpha-glutamyl peptides
Products: -
Products: -
?
additional information
?
-
-
Substrates: enzyme does not show any transpeptidase activity
Products: -
Products: -
?
additional information
?
-
-
Substrates: enzyme does not show any transpeptidase activity
Products: -
Products: -
?
additional information
?
-
-
Substrates: the maximal velocity decreases in the order methothrexate hexaglutamate, methotrexate tetraglutamate, methotrexate pentaglutamate, methotrexate triglutamate
Products: -
Products: -
?
additional information
?
-
-
Substrates: soluble enzyme has a requirement for sulfhydryl groups in the active site
Products: -
Products: -
?
additional information
?
-
-
Substrates: the intracellular enzyme shows the greatest affinity for the complete folic acid molecule with longer glutamate chains
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme is a cysteine peptidase
Products: -
Products: -
?
additional information
?
-
-
Substrates: the intracellular enzyme cleaves both terminal and internal gamma-glutamate linkages, in contrast the brush-border enzyme catalyzes the hydrolysis of only terminal gamma-glutamate linkages
Products: -
Products: -
?
additional information
?
-
-
Substrates: progressively removes gamma-glutamyl residues at acidic pH from pteroylpoly-gamma-glutamate to yield pteroyl-alpha-glutamate (folic acid) and free gamma-glutamic acid, highly specific for the gamma-glutamyl bond, but not for the C-terminal amino acid (leaving group), action on gamma-glutamyl bonds is independent of an N-terminal pteroyl moiety
Products: -
Products: -
?
additional information
?
-
-
Substrates: key enzyme in the metabolism of folic acid and the pharmacology of many antifolate drugs
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme cleaves gamma-polyglutamate chains attached to folates and anti-folates after they enter mammalian cells, the enzyme plays an important role in folate homeostasis and confers resistance to anti-folates, especially methotrexate, the drugs are dependent on polyglutamylation for activity, overview
Products: -
Products: -
?
additional information
?
-
Substrates: the CpG island methylator phenotype in colorectal cancer is defined as concomitant and frequent hypermethylation of CpG islands within gene promoter regions, and is correlated with low expression levels of the enzyme in primary cancer cells, GGH is involved in the folate pathway and in the development and/or progression of this phenotype, CIMP+-related clinicopathological and molecular features, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: GGH catalyzes degradation of the active polyglutamates of natural folates and the antifolate methotrexate
Products: -
Products: -
?
additional information
?
-
-
Substrates: no hydrolysis of gamma-glutamyl tripeptide
Products: -
Products: -
?
additional information
?
-
-
Substrates: no hydrolysis of N-carbobenzoxyphenylalanyl-alanine
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme cleaves gamma-polyglutamate chains attached to folates and anti-folates after they enter mammalian cells, the enzyme plays an important role in folate homeostasis and confers resistance to anti-folates, especially methotrexate
Products: -
Products: -
?
additional information
?
-
-
Substrates: endopeptidase activity
Products: -
Products: -
?
additional information
?
-
-
Substrates: no hydrolysis of poly-alpha-glutamate
Products: -
Products: -
?
additional information
?
-
-
Substrates: protein-associated poly-gamma-glutamates are poor substrates
Products: -
Products: -
?
additional information
?
-
-
Substrates: no hydrolysis of 4-amino-benzoyl-gamma-glutamate
Products: -
Products: -
?
additional information
?
-
Substrates: key enzyme in the metabolism of folic acid and the pharmacology of many antifolate drugs
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme cleaves gamma-polyglutamate chains attached to folates and anti-folates after they enter mammalian cells, the enzyme plays an important role in folate homeostasis and confers resistance to anti-folates, especially methotrexate
Products: -
Products: -
?
additional information
?
-
-
Substrates: either deacylation or rearrangement of the enzyme-product complex is rate-limiting in the isopeptide hydrolysis reaction
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase. Cleaves PteGlu5 more efficiently than pABAGlu5
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase. Cleaves PteGlu5 more efficiently than pABAGlu5
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase. Cleaves PteGlu5 more efficiently than pABAGlu5
Products: -
Products: -
?
additional information
?
-
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase. Cleaves PteGlu5 more efficiently than pABAGlu5
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase
Products: -
Products: -
?
additional information
?
-
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase. Cleaves PteGlu5 more efficiently than p-aminobenzoylpentaglutamate
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase. Cleaves PteGlu5 more efficiently than p-aminobenzoylpentaglutamate
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase. Cleaves PteGlu5 more efficiently than p-aminobenzoylpentaglutamate
Products: -
Products: -
?
additional information
?
-
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase. Cleaves PteGlu5 more efficiently than p-aminobenzoylpentaglutamate
Products: -
Products: -
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
folic acid pentaglutamate + H2O
?
Substrates: PteGlu5
Products: -
Products: -
?
p-aminobenzoylpentaglutamate + H2O
?
Substrates: pABAGlu5
Products: -
Products: -
?
glutathione + H2O
?
-
Substrates: enzyme hydrolyses the physiological antioxidant glutathione, suggesting an involvement of the enzyme in the cellular defense mechanism against oxidative stress
Products: -
Products: -
?
glutathione + H2O
?
-
Substrates: enzyme hydrolyses the physiological antioxidant glutathione, suggesting an involvement of the enzyme in the cellular defense mechanism against oxidative stress
Products: -
Products: -
?
polyglutamyl-folate + H2O
monoglutamyl folate + glutamate
-
Substrates: -
Products: -
Products: -
?
polyglutamyl-folate + H2O
monoglutamyl folate + glutamate
-
Substrates: -
Products: -
Products: -
?
polyglutamyl-folate + H2O
monoglutamyl folate + glutamate
Substrates: -
Products: -
Products: -
?
polyglutamyl-folate + H2O
monoglutamyl folate + glutamate
-
Substrates: -
Products: -
Products: -
?
polyglutamyl-folate + H2O
monoglutamyl folate + glutamate
-
Substrates: gamma-glutamyl hydrolase, not glutamate carboxypeptidase II, hydrolyzes dietary folate in rat small intestine
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: the enzyme is responsible for the intracellular cleavage of poly-gamma-glutamates
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: the enzyme is suggested to be involved in the destruction of microorganisms in granulocytes during phagocytosis
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: central enzyme in folyl and antifolylpoly-gamma-glutamate metabolism
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: key enzyme in the maintenance of cellular folylpolyglutamate concentration
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: central enzyme in folyl and antifolyl poly-gamma-glutamate metabolism
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: folate conjugase in the brush-border may accomplish the initial digestion of the dietary pteroylpolyglutamates
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: the enzyme progressively hydrolyzes glutamyl units from pteroylpolyglutamate, leaving pteroylmonoglutamate as the folate form available for intestinal transport
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: possible contribution of biliary enzyme to intestinal absorption of folate polyglutamates
Products: -
Products: -
?
pteroylpolyglutamate + H2O
?
-
Substrates: pancreatic enzyme may act in vivo in folate digestion and absorption to initiate the deconjugation of dietary pteroylpolyglutamate prior to the action of jejunal brush-border enzyme
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme specifically cleaves D- and L-polyglutamic acid, preferred to entirely of poly-D-glutamic acid, a component of the capsule produced by several strains of Bacillus subtilis, the enzyme has minimal activity in degrading Bacillus anthracis and to remove the capsule from the surface of bacilli, the poly-gamma-D-glutamic acid capsule, no effect on RAW264.7 murine macrophage phagocytosis, and only minimal enhancement of human host neutrophil killing
Products: -
Products: -
?
additional information
?
-
Substrates: hydrolysis of the gamma-glutamate bond, resulting in folate-mono-Glu
Products: -
Products: -
?
additional information
?
-
-
Substrates: hydrolysis of the gamma-glutamate bond, resulting in folate-mono-Glu
Products: -
Products: -
?
additional information
?
-
Substrates: hydrolysis of the gamma-glutamate bond, resulting in folate-mono-Glu
Products: -
Products: -
?
additional information
?
-
-
Substrates: key enzyme in the metabolism of folic acid and the pharmacology of many antifolate drugs
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme cleaves gamma-polyglutamate chains attached to folates and anti-folates after they enter mammalian cells, the enzyme plays an important role in folate homeostasis and confers resistance to anti-folates, especially methotrexate, the drugs are dependent on polyglutamylation for activity, overview
Products: -
Products: -
?
additional information
?
-
Substrates: the CpG island methylator phenotype in colorectal cancer is defined as concomitant and frequent hypermethylation of CpG islands within gene promoter regions, and is correlated with low expression levels of the enzyme in primary cancer cells, GGH is involved in the folate pathway and in the development and/or progression of this phenotype, CIMP+-related clinicopathological and molecular features, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: GGH catalyzes degradation of the active polyglutamates of natural folates and the antifolate methotrexate
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme cleaves gamma-polyglutamate chains attached to folates and anti-folates after they enter mammalian cells, the enzyme plays an important role in folate homeostasis and confers resistance to anti-folates, especially methotrexate
Products: -
Products: -
?
additional information
?
-
Substrates: key enzyme in the metabolism of folic acid and the pharmacology of many antifolate drugs
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme cleaves gamma-polyglutamate chains attached to folates and anti-folates after they enter mammalian cells, the enzyme plays an important role in folate homeostasis and confers resistance to anti-folates, especially methotrexate
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase. Cleaves PteGlu5 more efficiently than pABAGlu5
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase. Cleaves PteGlu5 more efficiently than pABAGlu5
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase. Cleaves PteGlu5 more efficiently than pABAGlu5
Products: -
Products: -
?
additional information
?
-
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase. Cleaves PteGlu5 more efficiently than pABAGlu5
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase
Products: -
Products: -
?
additional information
?
-
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase. Cleaves PteGlu5 more efficiently than p-aminobenzoylpentaglutamate
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase. Cleaves PteGlu5 more efficiently than p-aminobenzoylpentaglutamate
Products: -
Products: -
?
additional information
?
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase. Cleaves PteGlu5 more efficiently than p-aminobenzoylpentaglutamate
Products: -
Products: -
?
additional information
?
-
-
Substrates: folates typically have gamma-linked polyglutamyl tails that make them better enzyme substrates and worse transport substrates than the unglutamylated forms. The tail can be shortened or removed by the vacuolar enzyme gamma-glutamyl hydrolase. Cleaves PteGlu5 more efficiently than p-aminobenzoylpentaglutamate
Products: -
Products: -
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
Mg2+
Mn2+
Zinc
Zn2+
additional information
Zn2+
a zinc-binding motif, His-Glu-His, is present at the C-terminal end of the beta-sheet. The enzyme has a catalytic center containing a zinc ion and an overall topology resembling mammalian carboxypeptidase A and related enzymes
additional information
-
Ca2+, Co2+, Mg2+, Mn2+, and Ni2+ at 5 mM have little effect on enzyme activity
additional information
-
in cationic buffers, the enzyme has a higher activity than in anionic buffers of the same ionic strength and pH
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
substituted and reduced pteroylglutamate
-
0.1 mM: not, 30% inhibition at 1.0 mM
iodoacetate
-
inhibition of wild-type enzyme and mutant enzymes C19A, C124A and C290A
p-hydroxymercuribenzoate
-
soluble intracellular enzyme is inhibited, membrane-bound brush-border enzyme not
additional information
-
no inhibition by EDTA, PMSF, or iodoacetic acid at 5 mM
-
additional information
-
the active centre is not blocked by thiol reagents or fluorophosphates
-
additional information
-
no inhibition by diphenylhydantoin or salicylazosulfapyridine; no inhibition by ethanol
-
additional information
-
no inhibition by alpha-diglutamic acid; no inhibition by alpha-triglutamic acid; no inhibition by glutamic acid
-
additional information
-
no inhibition by anionic polysaccharides; no inhibition by pteroic acid; no inhibition by pteroylglutamate
-
additional information
-
no inhibition by diisopropylfluorophosphate
-
additional information
-
no inhibition by competitive inhibitors of serine and cysteine proteinases; no inhibition by phosphoramidon
-
additional information
-
no inhibition by anionic polysaccharides; no inhibition by pteroic acid; no inhibition by pteroylglutamate
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
erythromycin slightly stimulates the enzyme-mediated phagocytosis
-
additional information
-
preincubation of the enzyme at 25 °C for 2 h is necessary to obtain maximal activity
-
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Arthritis, Rheumatoid
Erythrocyte methotrexate-polyglutamate assay using fluorescence polarization immunoassay technique: application to the monitoring of patients with rheumatoid arthritis.
Breast Neoplasms
Folate conjugase activity in the plasma and tumors of breast-cancer patients.
Breast Neoplasms
Identification of single nucleotide polymorphisms in the human gamma-glutamyl hydrolase gene and characterization of promoter polymorphisms.
Breast Neoplasms
Membrane Glycoproteins Associated with Breast Tumor Cell Progression Identified by a Lectin Affinity Approach.
Carcinoma
Overexpression, genomic amplification and therapeutic potential of inhibiting the UbcH10 ubiquitin conjugase in human carcinomas of diverse anatomic origin.
Carcinoma, Ductal
Folate conjugase activity in the plasma and tumors of breast-cancer patients.
Carcinoma, Hepatocellular
Effects of gamma-glutamyl hydrolase on folyl and antifolylpolyglutamates in cultured H35 hepatoma cells.
Carcinoma, Hepatocellular
Identification, cloning, and sequencing of a cDNA coding for rat gamma-glutamyl hydrolase.
Carcinoma, Hepatocellular
The properties and function of gamma-glutamyl hydrolase and poly-gamma-glutamate.
Carcinoma, Hepatocellular
The properties of the secreted gamma-glutamyl hydrolases from H35 hepatoma cells.
Carcinoma, Hepatocellular
The role of folylpolyglutamate synthetase and gamma-glutamyl hydrolase in altering cellular folyl- and antifolylpolyglutamates.
Colorectal Neoplasms
Altered gene expression of folate enzymes in adjacent mucosa is associated with outcome of colorectal cancer patients.
Colorectal Neoplasms
Low expression of gamma-glutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype.
Fanconi Anemia
Deficiency of the Fanconi anemia E2 ubiqitin conjugase UBE2T only partially abrogates Alu-mediated recombination in a new model of homology dependent recombination.
folate gamma-glutamyl hydrolase deficiency
Significance of subnormal red-cell folate in thalassaemia.
Glioblastoma
Overexpression, genomic amplification and therapeutic potential of inhibiting the UbcH10 ubiquitin conjugase in human carcinomas of diverse anatomic origin.
Iron Deficiencies
A lysine-63-linked ubiquitin chain-forming conjugase, UBC13, promotes the developmental responses to iron deficiency in Arabidopsis roots.
Leukemia
gamma-Glutamyl hydrolase and folylpolyglutamate synthetase activities predict polyglutamylation of methotrexate in acute leukemias.
Leukemia
Honokiol induces proteasomal degradation of AML1-ETO oncoprotein via increasing ubiquitin conjugase UbcH8 expression in leukemia.
Leukemia
Identification of single nucleotide polymorphisms in the human gamma-glutamyl hydrolase gene and characterization of promoter polymorphisms.
Leukemia
Role of folylpolyglutamate synthetase and folylpolyglutamate hydrolase in methotrexate accumulation and polyglutamylation in childhood leukemia.
Leukemia
[Separation of methotrexate-polyglutamates by capillary electrophoresis and its application to the measurement of gamma-glutamyl hydrolase activity in human leukemia cells in culture]
Multiple Myeloma
Amplification and overexpression of E2 ubiquitin conjugase UBE2T promotes homologous recombination in multiple myeloma.
Neoplasms
A novel class of monoglutamated antifolates exhibits tight-binding inhibition of human glycinamide ribonucleotide formyltransferase and potent activity against solid tumors.
Neoplasms
A randomized, double-blind, phase II study of two doses of pemetrexed as first-line chemotherapy for advanced breast cancer.
Neoplasms
Altered gene expression of folate enzymes in adjacent mucosa is associated with outcome of colorectal cancer patients.
Neoplasms
Characterization of the human gamma-glutamyl hydrolase promoter and its gene expression in human tissues and cancer cell lines.
Neoplasms
Gene expression levels of gamma-glutamyl hydrolase in tumor tissues may be a useful biomarker for the proper use of S-1 and tegafur-uracil/leucovorin in preoperative chemoradiotherapy for patients with rectal cancer.
Neoplasms
Hydrolytic cleavage of methotrexate gamma-polyglutamates by folylpolyglutamyl hydrolase derived from various tumors and normal tissues of the mouse.
Neoplasms
Karyotypic abnormalities create discordance of germline genotype and cancer cell phenotypes.
Neoplasms
Overexpression, genomic amplification and therapeutic potential of inhibiting the UbcH10 ubiquitin conjugase in human carcinomas of diverse anatomic origin.
Neoplasms
Predicting clinical outcome of 5-fluorouracil-based chemotherapy for colon cancer patients: is the CpG island methylator phenotype the 5-fluorouracil-responsive subgroup?
Neoplasms
[Separation of methotrexate-polyglutamates by capillary electrophoresis and its application to the measurement of gamma-glutamyl hydrolase activity in human leukemia cells in culture]
Neuroendocrine Tumors
Identification of carboxypeptidase E and gamma-glutamyl hydrolase as biomarkers for pulmonary neuroendocrine tumors by cDNA microarray.
Parkinson Disease
The SUMO Conjugase Ubc9 Protects Dopaminergic Cells from Cytotoxicity and Enhances the Stability of ?-Synuclein in Parkinson's Disease Models.
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Epigenetic regulation of human gamma-glutamyl hydrolase activity in acute lymphoblastic leukemia cells.
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Influence of genetic polymorphisms of FPGS, GGH, and MTHFR on serum methotrexate levels in Chinese children with acute lymphoblastic leukemia.
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Methotrexate intracellular disposition in acute lymphoblastic leukemia: a mathematical model of gamma-glutamyl hydrolase activity.
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Polymorphisms of the gamma-glutamyl hydrolase gene and risk of relapse to acute lymphoblastic leukemia in Mexico.
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Role of folylpolyglutamate synthetase and folylpolyglutamate hydrolase in methotrexate accumulation and polyglutamylation in childhood leukemia.
Psoriasis
Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms.
Rectal Neoplasms
Gene expression levels of gamma-glutamyl hydrolase in tumor tissues may be a useful biomarker for the proper use of S-1 and tegafur-uracil/leucovorin in preoperative chemoradiotherapy for patients with rectal cancer.
Sarcoma
gamma-Glutamyl hydrolase from human sarcoma HT-1080 cells: characterization and inhibition by glutamine antagonists.
Sarcoma
Increased activity of gamma-glutamyl hydrolase in human sarcoma cell lines: a novel mechanism of intrinsic resistance to methotrexate (MTX).
Sprue, Tropical
Folic acid conjugase in normal human plasma and in the plasma of patients with tropical sprue.
Stomach Neoplasms
High gamma-glutamyl hydrolase and low folylpolyglutamate synthetase expression as prognostic biomarkers in patients with locally advanced gastric cancer who were administrated postoperative adjuvant chemotherapy with S-1.
Tuberculosis, Pulmonary
Serum protein gamma-glutamyl hydrolase, Ig gamma-3 chain C region, and haptoglobin are associated with the syndromes of pulmonary tuberculosis in traditional Chinese medicine.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0076
L-glutamic acid gamma-(4-nitroanilide)
-
Vmax: 0.36 micromol/min/mg
additional information
additional information
-
Km of methotrexate polyglutamates
-
additional information
additional information
-
Michaelis-Menten kinetics, detailed steady-state kinetics and partial pre-steady-state kinetics, stopped-flow method, overview
-
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
pteroyltriglutamate: 732 gamma-glutamyl bonds are cleaved per min per mol of enzyme
-
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
assay using pteroyl-labeled substrates and selective short-term bacterial uptake for product determination
additional information
-
highest activity in the postprandial duodenal luminal fluid at pH 4.5
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
4.5
7.8
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
4.5 - 6.5
-
4.5 is the pH optimum, while pH 6.5 is the in vivo reaction temperature
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
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TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
NBRC16449, CMU29, isolated from Thai Thua-nao, a natto-like fermented soybean food
-
-
brenda
IFO 12515, 2 poly(glutamic acid) hydrolases: PGH-I and PGH-II
-
-
brenda
-
647293, 647295, 647302, 647305, 647306, 647307, 647308, 647313, 647316, 647317, 647318, 647319, 647320, 668884, 683039, 683179
-
-
brenda
two separate folate conjugase activities in jejunal mucosa: one membrane-bound and concentrated in the brush-border and the other soluble and intracellular
-
-
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
GGH expression is significantly higher in gastric cancer tissue than in adjacent normal mucosa
brenda
GGH expression is significantly higher in gastric cancer tissue than in adjacent normal mucosa
brenda
-
pulmonary, expression of gamma-glutamyl hydrolase correlates with poor prognosis
brenda
primary, low enzyme expression level in cells from the CpG island methylator phenotype, overview
brenda
-
tomato cultivars Periyakulam-1 (PKM-1) displays high folate and Arka Vikas (AV) has low folate levels. The transcript levels of isoforms GGH1, GGH2, and GGH3 in PKM-1 are significantly lower than in AV at the red-ripe stage
brenda
-
gamma-glutamyl hydrolase overexpression decreases global DNA methylation and DNA methyltransferase activity, while gamma-glutamyl hydrolase inhibition increases global DNA methylation and DNA methyltransferase activity. gamma-Glutamyl hydrolase modulation influences CpG promoter DNA methylation and gene expression involved in important biological pathways including cell cycle, cellular development, and cellular growth and proliferation
brenda
-
gamma-glutamyl hydrolase overexpression decreases global DNA methylation and DNA methyltransferase activity, while gamma-glutamyl hydrolase inhibition increases global DNA methylation and DNA methyltransferase activity. gamma-Glutamyl hydrolase modulation influences CpG promoter DNA methylation and gene expression involved in important biological pathways including cell cycle, cellular development, and cellular growth and proliferation
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
mainly, only minor amounts in the vacuolar and mitochondrial fraction
brenda
Highest Expressing Human Cell Lines
Cell Line LinksPlease wait a moment until the data is sorted. This message will disappear when the data is sorted.
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
malfunction
-
the association of -401C/T and +452C/T polymorphisms of gamma-glutamyl hydrolase and the risk of relapse to acute lymphoblastic leukemia is investigated. An association between the -401C/T polymorphism and the risk of relapse is found, patients with the -401T/T genotype have 10.83 more chance of a relapse of leukemia. No association is found between the +452C/T polymorphism and the risk of relapse
malfunction
intact GGH is not indispensable for the chemosensitivity and growth of acute lymphoblastic leukemia (ALL) cells, whereas GGH lacking N-terminal signal peptide confers the significant drug resistance of ALL cells to the antifolates MTX and RTX. ALL cells harboring GGH lacking the N-terminal signal peptide show high susceptibility to the change in folates. The loss of signal peptide enhances intracellular retention of GGH and its lysosomal disposition
physiological function
-
gamma-Glutamyl hydrolase modulation-induced changes in total intracellular folate concentrations and content of long-chain folyl-polyglutamates are associated with functionally significant DNA methylation alterations in important biological pathways including cell cycle, cellular development, and cellular growth and proliferation
physiological function
-
overexpression of gamma-glutamyl hydrolase significantly decreases chemosensitivity of MDA-MB-435 cells to 5-fluorouracil and methotrexate at all folate concentrations as expected. In contrast, in HCT116 cells this predicted effect is observed only at very high folate concentration, and as the folate concentration decreases this effect becomes null or paradoxically increases. Inhibition of gamma-glutamyl hydrolase significantly increases chemosensitivity of both cancer cells to 5-fluorouracil at all folate concentrations. gamma-Glutamyl hydrolase inhibition significantly decreases chemosensitivity of both cancer cells to methotrexate at all folate concentrations. In both modulation systems and cell lines, the magnitude of chemosensitivity effect incrementally increases as folate concentration increases
physiological function
the enzymes gamma-glutamyl hydrolase (GGH) and folylpolyglutamate synthetase (FPGS) regulate intracellular folate concentrations needed for cell proliferation, DNA synthesis, and repair
physiological function
the overexpression of GGH in colon cancer-derived cell lines inhibits PKM, GLUT1, and LDHA expression and decreases the extracellular lactate content and intracellular ATP level. The opposite effects are obtained by GGH silencing
Show AA Sequence and Transmembrane Helices (3444 entries)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
110000
18000
-
1 * 43000 + 1 * 18000, SDS-PAGE of 2-mercaptoethanol treated enzyme, the 2 disulfide-linked polypeptide chains are independently active
21000
-
SDS-PAGE, shorter subunit after post-translational modification
35938
-
2 * 35938, recombinant His-tagged enzyme, dynamic light scattering, analytical ultracentrifugation, and sedimentation velocity measurement, nondissociating homodimer, homodimer formation is required for folding into the active conformation, overview
40000
43000
-
1 * 43000 + 1 * 18000, SDS-PAGE of 2-mercaptoethanol treated enzyme, the 2 disulfide-linked polypeptide chains are independently active
61000
-
SDS-PAGE, precursor homotetrameric protein of 61000 Da per subunit
71880
-
recombinant His-tagged enzyme, dynamic light scattering, analytical ultracentrifugation, and sedimentation velocity measurement
80000
additional information
40000
-
SDS-PAGE, shorter subunit after post-translational modification
additional information
-
the enzyme shows 2 peaks on gel filtration: MW 50000 Da and 25000 Da
additional information
recombinant NH-zgammaGH and zgammaGH appear on SDS-PAGE in the ranges of their estimated size of 92 and 33 kDa, respectively
additional information
-
recombinant NH-zgammaGH and zgammaGH appear on SDS-PAGE in the ranges of their estimated size of 92 and 33 kDa, respectively
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
heterodimer
heterotetramer
homodimer
homotetramer
tetramer
dimer
-
1 * 43000 + 1 * 18000, SDS-PAGE of 2-mercaptoethanol treated enzyme, the 2 disulfide-linked polypeptide chains are independently active
dimer
-
2 * 35938, recombinant His-tagged enzyme, dynamic light scattering, analytical ultracentrifugation, and sedimentation velocity measurement, nondissociating homodimer, homodimer formation is required for folding into the active conformation, overview
dimer
nondissociating homodimer, homodimer formation is required for folding into the active conformation, overview
heterodimer
the homodimer is catalytically inactive
homodimer
zgammaGH. NH-zgammaGH is a tetramer. It seems that the presence of the N-terminal Nus and His-tag interferes with the quaternary structure of zgammaGH
homodimer
-
zgammaGH. NH-zgammaGH is a tetramer. It seems that the presence of the N-terminal Nus and His-tag interferes with the quaternary structure of zgammaGH
-
tetramer
-
2 * 40000 + 2 * 21000, SDS-PAGE. The unprocessed enzyme forms an already active homotetramer, whereas the mature enzyme is a fully active compact alpha2beta2-heterotetramer
tetramer
-
2 * 40000 + 2 * 21000, SDS-PAGE. The unprocessed enzyme forms an already active homotetramer, whereas the mature enzyme is a fully active compact alpha2beta2-heterotetramer
-
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
proteolytic modification
glycoprotein
-
from cancer cells, the enzyme is glycosylated at Asn139, Asn179, partially at Asn283, but not at Asn92
proteolytic modification
-
the enzyme is synthesized as a precursor homotetrameric protein of 60 kDa per subunit, and undergoes an internal post-translational cleavage of the 60 kDa monomer into 40 kDa and 21 kDa shorter subunits, which are then assembled into an active heterotetramer composed of two 40 kDa and two 21 kDa subunits
proteolytic modification
-
precursor homotetrameric protein of 61000 Da per subunit undergoes an internal post-translational cleavage into 40 and 21 kDa shorter subunits, which are then assembled into an active heterotetramer composed of two 40 and two 21 kDa subunits
proteolytic modification
-
the enzyme is synthesized as a precursor homotetrameric protein of 60 kDa per subunit, and undergoes an internal post-translational cleavage of the 60 kDa monomer into 40 kDa and 21 kDa shorter subunits, which are then assembled into an active heterotetramer composed of two 40 kDa and two 21 kDa subunits
-
proteolytic modification
-
precursor homotetrameric protein of 61000 Da per subunit undergoes an internal post-translational cleavage into 40 and 21 kDa shorter subunits, which are then assembled into an active heterotetramer composed of two 40 and two 21 kDa subunits
-
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
to 1.9 A resolution. A zinc-binding motif, His-Glu-His, is present at the C-terminal end of the beta-sheet. The enzyme has a catalytic center containing a zinc ion and an overall topology resembling mammalian carboxypeptidase A and related enzymes
wild-type and mutants C108A and H218N in complex with substrate methotrexate pentaglutamate and product methotrexate glutamate, to 1.9 to 2.4 A resolution. The side chain of residue Phe20 and the 6-methylpterin ring of methotrexate pentaglutamate invoke pi-pi interactions to promote distinct concerted conformational alterations involving about 90° rotations in the complexes with the C108A and H218N mutant proteins
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
H218N
complete loss of hydrolytic activity. Residue His218 alone suffices to catalyze the hydrolysis of the gamma-glutamate bond in gamma-glutamyl hydrolase
T353A
C124A
-
Km-value for methotrexate diglutamate is not significantly different from the Km-value of the wild-type enzyme. Specific activity is significantly lower than that of the wild-type enzyme, but the mutant protein has a higher amount of contaminating protein
C19A
-
Km-value for methotrexate diglutamate is not significantly different from the Km-value of the wild-type enzyme. Specific activity is significantly lower than that of the wild-type enzyme, but the mutant protein has a higher amount of contaminating protein
C290A
-
Km-value for methotrexate diglutamate is not significantly different from the Km-value of the wild-type enzyme
E222A
-
maximal velocity with methotrexate diglutamate is reduced 6fold relative to the wild-type enzyme
H171N
-
maximal velocity with methotrexate diglutamate is reduced 250fold relative to the wild-type enzyme
T127I
-
distribution of the naturally occuring T127I polymorphism of the enzyme in a Japanese population, genotype distribution and allele frequency, Hardy-Weinberg equilibrium, comparison to Caucasians and in African-Americans populations, overview
additional information
T353A
-
mutation of the N-terminal residue of the 21 kDa subunit, abolishes the post-translational cleavage of the pro-enzyme, but does not completely block the hydrolytic action
T353A
-
mutation abolishes the post-translational cleavage of the pro-enzyme, but does not completely block the hydrolytic action
T353A
-
mutation of the N-terminal residue of the 21 kDa subunit, abolishes the post-translational cleavage of the pro-enzyme, but does not completely block the hydrolytic action
-
T353A
-
mutation abolishes the post-translational cleavage of the pro-enzyme, but does not completely block the hydrolytic action
-
additional information
-
the recombinant glycosylated enzyme forms very stable dimeric complexes with the recombinant His-tagged rat enzyme, overview
additional information
the enzyme forms very stable dimeric complexes with the glycosylated human enzyme, overview
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pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
40
45
50
65
45
-
pH 7.8, GthGT retains 83% of the activity after 24 h incubation
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
affinity chromatography
after induction with isopropyl thiogalactoside, the enzyme is purified with a Ni-Sepharose column
partial
recombinant N-terminally His-tagged enzyme from Hi5 insect cells, and non-tagged glycosylated enzyme from Hi5 insect cells by anion exchange chromatography
-
recombinant proteins are purified by Ni2+ affinity chromatography
recombinant proteins are purified by Ni2+ affinity chromatography; in the case of LeGGH1, an additional cation exchange step is required
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cloned and inserted into a pET43.1a vector via SmaI and EcoRI sites and expressed in Rosetta (DE3) cells as a Nus-His-tag fusion enzyme (NH-zgammaGH)
expressed as a fusion protein containing a C-terminal His-tag in Escherichia coli
-
expression in Escherichia coli
expression the N-terminally His-tagged and non-tagged glycosylated enzyme in Hi5 insect cells
-
gene GGH, DNA and amino acid sequence determination and analysis, genotyping, overview
-
gene GGH, DNA and amino acid sequence determination and anaylsis, expression analysis, GGH promoter methylation is not a cause of GGH downregulation in CIMP+ colorectal cancer
GGH activity is directly related to GGH messenger RNA expression in acute lymphoblastic leukemia cells of patients with a wild-type germline GGH genotype, identification of two CpG islands, CpG1 and CpG2, in the region extending from the GGH promoter through the first exon and into intron 1, methylation of both CpG islands in the GGH promoter is associated with significantly reduced GGH mRNA expression and catalytic activity and with significantly higher accumulation of MTX polyglutamates in the cells, methylation of CpG1 is leukemia-cell specific and has a pronounced effect on GGH expression, whereas methylation of CpG2 is common in leukemia cells and normal leukocytes but does not significantly alter GGH expression, expression analysis, overview
-
when coexpressed in Escherichia coli, homodimer is catalytically inactive. LeGGH3 forms heterodimers with LeGGH1 or LeGGH2 that has one-half the activity of the matching homodimer
when coexpressed in Escherichia coli, LeGGH1 forms heterodimers with an intermediate bond cleavage preference
when coexpressed in Escherichia coli, LeGGH2 forms heterodimers with an intermediate bond cleavage preference
wild-type and mutant enymes C19A, C110A, C124A and C290A are expressed in Escherichia coli
-
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
GGH expression is low in uterine corpus endometrial carcinomas CHOL, KICH, KIRC, KIRP, KIRP, and LAML
GGH expression is significantly higher than control in 22 uterine corpus endometrial carcinomas, including ACC, BLCA, BRCA, CESC, COAD,DLBC, ESCA, GBM, HNSC, LGG, LIHC, LUAD, LUSC, OV, PAAD, READ, SKCM, STAD, THCA, THYM, UCEC, and UCS
reduced expression of GGH is a predictive factor of a reduced folate level after leucovorin administration in colorectal cancer
the transcript levels of isoforms GGH1, GGH2, and GGH3 in PKM-1 are significantly lower than in AV at the red-ripe stage
-
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
agriculture
-
tomato cultivars Periyakulam-1 (PKM-1) displays high folate and Arka Vikas (AV) has low folate levels. The transcript levels of isoforms GGH1, GGH2, and GGH3 in PKM-1 are significantly lower than in AV at the red-ripe stage. In both cultivars, the activity of GGH is highest at the mature green stage and declines with ripening progression. At breaker stage, GGH activity is significantly high in PKM-1, whereas at red-ripe, the GGH activity is significantly low in PKM-1 fruits
analysis
diagnostics
high gamma-glutamyl hydrolase and low folylpolyglutamate synthetase expression is a useful independent predictor of poor outcomes in stage II/III gastric cancer patients undergoing postoperative adjuvant chemotherapy with S-1
medicine
analysis
-
trienzyme extraction is a combined enzymatic digestion by Pronase, alpha-amylase, and conjugase, i.e. gamma-glutamyl hydrolase, to liberate the carbohydrate and protein-bound folates from food matrices prior to total folate analysis by microbiological assay using Lactobacillus casei ssp. rhamnosus, ATCC 7469, determine the contribution of the enzymes to the growth response, the extraction method is used in AOAC Official Method 2004.05 for the folate analysis of cereal foods
analysis
folate analysis. Isoform GGH2 is able to completely deconjugate folates using 50-100 microg/g of sample for 1 h at 37°C in all matrices tested. It removes the tails of folylpolyglutamates from tomato fruit, black bean and peanut seeds, and alfalfa sprouts extracts
medicine
-
gamma-glutamyl hydrolase as biomarkers for pulmonary neuroendocrine tumors by cDNA microarray. Expression of gamma-glutamyl hydrolase correlates with poor prognosis
medicine
the relationships between the reduced folate levels in the colorectal cancer tissue after leucovorin administration and the gene-expression levels of folate-metabolizing enzymes and folate transporters is investigated. A multivariate logistic regression analysis reveals that low gamma-glutamyl hydrolase gene expression is a predictive factor for a high reduced folate level after leucovorin administration
medicine
-
genoproteomic mining of urothelial cancer suggests gamma-glutamyl hydrolase and diazepam-binding inhibitor as putative urinary markers of outcome after chemotherapy
medicine
-
overexpression of gamma-glutamyl hydrolase significantly decreases chemosensitivity of MDA-MB-435 cells to 5-fluorouracil and methotrexate at all folate concentrations as expected. In contrast, in HCT116 cells this predicted effect is observed only at very high folate concentration, and as the folate concentration decreases this effect becomes null or paradoxically increases. Inhibition of gamma-glutamyl hydrolase significantly increases chemosensitivity of both cancer cells to 5-fluorouracil at all folate concentrations. gamma-Glutamyl hydrolase inhibition significantly decreases chemosensitivity of both cancer cells to methotrexate at all folate concentrations. In both modulation systems and cell lines, the magnitude of chemosensitivity effect incrementally increases as folate concentration increases
medicine
intact GGH is not indispensable for the chemosensitivity and growth of acute lymphoblastic leukemia (ALL) cells, whereas GGH lacking N-terminal signal peptide confers the significant drug resistance of ALL cells to the antifolates MTX and RTX. ALL cells harboring GGH lacking the N-terminal signal peptide show high susceptibility to the change in folates
medicine
gene encoding GGH is involved in glycolysis-cholesterol synthesis. GGH expression is upregulated in colon cancer and expression correlates with CD4+ T cell infiltration and longer overall survival
medicine
GGH affects uterine corpus endometrial carcinoma differentiation and immune infiltration. In the carcinomas, GGH expression is significantly associated with clinical stage, primary therapy outcome, race, BMI, histological grade, and surgical approach
medicine
differences in folic acid antagonist methotrexate degradation products (methotrexate polyglutamates MTXPGS) accumulation in liver and kidney cells are related to the differences in folylpolyglutamate synthetase (FPGS) and gamma-glutamyl hydrolase (GGH) expression. There is a positive correlation between the FPGS/GGH and the accumulation of MTXPGS in liver and kidney cells
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Rao, K.N.; Noronha, J.M.
Studies on the enzymatic hydrolysis of polyglutamyl folates by chicken liver folyl poly-gamma-glutamyl carboxypeptidase. I. Intracellular localization, purification and partial characterization of the enzyme
Biochim. Biophys. Acta
481
594-607
1977
Gallus gallus
brenda
Rao, K.N.; Noronha, J.M.
Studies on the enzymatic hydrolysis of polyglutamyl folates by chicken liver folyl poly-gamma-glutamyl carboxypeptidase. II. Structural studies
Biochim. Biophys. Acta
481
608-616
1977
Gallus gallus
brenda
Elsenhans, B.; Ahmad, O.; Rosenberg, I.H.
Isolation and characterization of pteroylpolyglutamate hydrolase from rat intestinal mucosa
J. Biol. Chem.
259
6364-6368
1984
Rattus norvegicus
brenda
Baugh, C.M.; Stevens, J.C.; Krumdieck, C.L.
Studies on gamma-glutamyl carboxypeptidase. I. The solid phase synthesis of analogs of polyglutamates of folic acid and their effects on human liver gamma-glutamyl carboxypeptidase
Biochim. Biophys. Acta
212
116-125
1970
Homo sapiens
brenda
Silink, M.; Reddel, R.; Bethel, M.; Rowe, P.B.
Gamma-glutamyl hydrolase conjugase. Purification and properties of the bovine hepatic enzyme
J. Biol. Chem.
250
5982-5994
1975
Bos taurus
brenda
Lakshmaiah, N.; Ramasastri, B.V.
Plasma folic acid conjugase
Methods Enzymol.
66
670-678
1980
Homo sapiens
brenda
Reisenauer, A.M.
Folate conjugase: two separate activities in human jejunum
Science
198
196-197
1977
Homo sapiens
brenda
Muro, T.; Nagamori, Y.; Okada, S.; Tominaga, Y.
Some properties and action of poly(glutamic acid) hydrolase II from Micromonospora melanosporea IFO 12515
Agric. Biol. Chem.
54
1065-1067
1990
Micromonospora melanosporea
brenda
Lin, S.; Rogiers, S.; Cossins, E.A.
gamma-Glutamyl hydrolase from pea cotyledons
Phytochemistry
32
1109-1117
1993
Lathyrus oleraceus
-
brenda
Wang, Y.; Nimec, Z.; Ryan, T.J.; Dias, J.A.; Galivan, J.
The properties of the secreted gamma-glutamyl hydrolases from H35 hepatoma cells
Biochim. Biophys. Acta
1164
227-235
1993
Rattus norvegicus
brenda
Tanaka, T.; Hiruta, O.; Futamura, T.; Uotani, K.; Satoh, A.; Taniguchi, M.; Or, S.
Purification and characterization of poly(g-glutamic acid) hydrolase from a filamentous fungus, Myrothecium sp. TM-4222
Biosci. Biotechnol. Biochem.
57
2148-2153
1993
Myrothecium sp., Myrothecium sp. TM-4222
-
brenda
Kferstein, H.; Jaenicke, L.
Gamma glutamyl carboxypeptidase from chicken pancreas
Hoppe-Seyler's Z. Physiol. Chem.
353
1153-1158
1972
Gallus gallus
brenda
Reisenauer, A.M.; Halsted, C.H.
Human jejunal brush border folate conjugase. Characteristics and inhibition by salicylazosulfapyridine
Biochim. Biophys. Acta
659
62-69
1981
Homo sapiens
brenda
Horne, D.W.; Krumdieck, C.L.; Wagner, C.
Properties of folic acid gamma-glutamyl hydrolase (conjugase) in rat bile and plasma
J. Nutr.
111
442-449
1981
Rattus norvegicus
brenda
Hartley, D.M.; Snodgrass, S.R.; Bradshaw, P.A.
The measurement of gamma-glutamyl hydrolase (conjugase) activity in rat brain
Neurochem. Res.
13
147-151
1988
Rattus norvegicus
brenda
Chandler, C.J.; Wang, T.T.Y.; Halsted, C.H.
Pteroylpolyglutamate hydrolase from human jejunal brush borders. Purification and characterization
J. Biol. Chem.
261
928-933
1986
Homo sapiens
brenda
Lavoie, A.; Tripp, E.; Hoffbrand, A.V.
Sephadex-gel filtration and heat stability of human jejunal and serum pteroylpolyglutamate hydrolase (folate conjugase). Evidence for two different forms
Biochem. Med.
13
1-6
1975
Homo sapiens
brenda
Wang, T.T.Y.; Chandler, C.J.; Halsted, C.H.
Intracellular pteroylpolyglutamate hydrolase from human jejunal mucosa. Isolation and characterization
J. Biol. Chem.
261
13551-13555
1986
Homo sapiens
brenda
Krungkrai, J.; Yuthavong, Y.; Webster, H.K.
High-performance liquid chromatographic assay for pteroylpolyglutamate hydrolase
J. Chromatogr.
417
47-56
1987
Homo sapiens
brenda
Elsenhans, B.; Selhub, J.; Rosenberg, I.H.
Assay of folylpolyglutamate hydrolase using pteroyl-labeled substrates and selective short-term bacterial uptake for product determination
Methods Enzymol.
66
663-666
1980
Rattus norvegicus
brenda
Rosenberg, I.H.; Saini, P.K.
Folylpolyglutamate endopeptidase from chicken intestine: isolation with the aid of affinity chromatography
Methods Enzymol.
66
667-670
1980
Gallus gallus
brenda
Leichter, J.; Butterworth, C.E.Jr.; Krumdieck, C.L.
Partial purification and some properties of pteroylpolyglutamate hydrolase (conjugase) from chicken pancreas
Proc. Soc. Exp. Biol. Med.
154
98-101
1977
Gallus gallus
brenda
Bhandari, S.D.; Gregory, J.F.3rd.; Renuart, D.R.; Merritt, A.M.
Properties of pteroylpolyglutamate hydrolase in pancreatic juice of the pig
J. Nutr.
120
467-475
1990
Sus scrofa
brenda
Gregory, J.F.3rd.; Ink, S.L.; Cerda, J.J.
Comparison of pteroylpolyglutamate hydrolase (folate conjugase) from porcine and human intestinal brush border membrane
Comp. Biochem. Physiol. B
88
1135-1141
1987
Sus scrofa, Homo sapiens
brenda
Samuels, L.L.; Goutas, L.J.; Priest, D.G.; Piper, J.R.; Sirotnak, F.M.
Hydrolytic cleavage of methotrexate gamma-polyglutamates by folylpolyglutamyl hydrolase derived from various tumors and normal tissues of the mouse
Cancer Res.
46
2230-2235
1986
Mus musculus
brenda
Jaegerstad, M.; Olsson, I.
Pteroylpolyglutamate hydrolase of human granulocytes. I. Partial purification and kinetic studies
Scand. J. Clin. Lab. Invest.
39
343-349
1979
Homo sapiens
brenda
Chave, K.J.; Auger, I.E.; Galivan, J.; Ryan, T.J.
Molecular modeling and site-directed mutagenesis define the catalytic motif in human gamma -glutamyl hydrolase
J. Biol. Chem.
275
40365-40370
2000
Homo sapiens
brenda
Galivan, J.; Ryan, T.J.; Chave, K.; Rhee, M.; Yao, R.; Yin, D.
Glutamyl hydrolase: pharmacological role and enzymatic characterization
Pharmacol. Ther.
85
207-215
2000
Homo sapiens
brenda
Chave, K.J.; Galivan, J.; Ryan, T.J.
Site-directed mutagenesis establishes cysteine-110 as essential for enzyme activity in human gamma-glutamyl hydrolase
Biochem. J.
343
551-555
1999
Homo sapiens
brenda
Rhee, M.S.; Lindau-Shepard, B.; Chave, K.J.; Galivan, J.; Ryan, T.J.
Characterization of human cellular gamma-glutamyl hydrolase
Mol. Pharmacol.
53
1040-1046
1998
Homo sapiens
brenda
Li, H.; Ryan, T.J.; Chave, K.J.; Van Roey, P.
Three-dimensional structure of human gamma -glutamyl hydrolase. A class I glatamine amidotransferase adapted for a complex substrate
J. Biol. Chem.
277
24522-24529
2002
Homo sapiens
brenda
He, P.; Varticovski, L.; Bowman, E.D.; Fukuoka, J.; Welsh, J.A.; Miura, K.; Jen, J.; Gabrielson, E.; Brambilla, E.; Travis, W.D.; Harris, C.C.
Identification of carboxypeptidase E and gamma-glutamyl hydrolase as biomarkers for pulmonary neuroendocrine tumors by cDNA microarray
Hum. Pathol.
35
1196-1209
2004
Homo sapiens
brenda
Orsomando, G.; de la Garza, R.D.; Green, B.J.; Peng, M.; Rea, P.A.; Ryan, T.J.; Gregory, J.F.; Hanson, A.D.
Plant gamma-glutamyl hydrolases and folate polyglutamates: characterization, compartmentation, and co-occurrence in vacuoles
J. Biol. Chem.
280
28877-28884
2005
Arabidopsis thaliana (O65355), Beta vulgaris, Lathyrus oleraceus
brenda
Cheng, Q.; Cheng, C.; Crews, K.R.; Ribeiro, R.C.; Pui, C.H.; Relling, M.V.; Evans, W.E.
Epigenetic regulation of human gamma-glutamyl hydrolase activity in acute lymphoblastic leukemia cells
Am. J. Hum. Genet.
79
264-274
2006
Homo sapiens
brenda
Scorpio, A.; Chabot, D.J.; Day, W.A.; Obrien, D.K.; Vietri, N.J.; Itoh, Y.; Mohamadzadeh, M.; Friedlander, A.M.
Poly-gamma-glutamate capsule-degrading enzyme treatment enhances phagocytosis and killing of encapsulated Bacillus anthracis
Antimicrob. Agents Chemother.
51
215-222
2007
Bacillus phage phiNIT1
brenda
Alexander, J.P.; Ryan, T.J.; Ballou, D.P.; Coward, J.K.
Gamma-glutamyl hydrolase: kinetic characterization of isopeptide hydrolysis using fluorogenic substrates
Biochemistry
47
1228-1239
2008
Rattus norvegicus
brenda
Eisele, L.E.; Chave, K.J.; Lehning, A.C.; Ryan, T.J.
Characterization of human gamma-glutamyl hydrolase in solution demonstrates that the enzyme is a non-dissociating homodimer
Biochim. Biophys. Acta
1764
1479-1486
2006
Homo sapiens, Rattus norvegicus (Q62867)
brenda
Hayashi, H.; Fujimaki, C.; Inoue, K.; Suzuki, T.; Itoh, K.
Genetic polymorphism of C452T (T127I) in human gamma-glutamyl hydrolase in a Japanese population
Biol. Pharm. Bull.
30
839-841
2007
Homo sapiens
brenda
Chunhachart, O.; Itoh, T.; Sukchotiratana, M.; Tanimoto, H.; Tahara, Y.
Characterization of gamma-glutamyl hydrolase produced by Bacillus sp. isolated from Thai Thua-nao
Biosci. Biotechnol. Biochem.
70
2779-2782
2006
Bacillus sp. (in: firmicutes)
brenda
Kawakami, K.; Ooyama, A.; Ruszkiewicz, A.; Jin, M.; Watanabe, G.; Moore, J.; Oka, T.; Iacopetta, B.; Minamoto, T.
Low expression of gamma-glutamyl hydrolase mRNA in primary colorectal cancer with the CpG island methylator phenotype
Br. J. Cancer
98
1555-1561
2008
Homo sapiens (Q92820)
brenda
Schneider, E.; Ryan, T.J.
Gamma-glutamyl hydrolase and drug resistance
Clin. Chim. Acta
374
25-32
2006
Homo sapiens, Mus musculus, Rattus norvegicus
brenda
Chen, L.; Eitenmiller, R.R.
Optimization of the trienzyme extraction for the microbiological assay of folate in vegetables
J. Agric. Food Chem.
55
3884-3888
2007
Gallus gallus
brenda
Shafizadeh, T.B.; Halsted, C.H.
gamma-Glutamyl hydrolase, not glutamate carboxypeptidase II, hydrolyzes dietary folate in rat small intestine
J. Nutr.
137
1149-1153
2007
Rattus norvegicus
brenda
Kao, T.T.; Chang, W.N.; Wu, H.L.; Shi, G.Y.; Fu, T.F.
Recombinant zebrafish gamma-glutamyl hydrolase exhibits properties and catalytic activities comparable with those of mammalian enzyme
Drug Metab. Dispos.
37
302-309
2009
Danio rerio (Q6NY42), Danio rerio, Danio rerio AB (Q6NY42)
brenda
Akhtar, T.A.; McQuinn, R.P.; Naponelli, V.; Gregory, J.F.; Giovannoni, J.J.; Hanson, A.D.
Tomato gamma-glutamylhydrolases: expression, characterization, and evidence for heterodimer formation
Plant Physiol.
148
775-785
2008
Solanum lycopersicum (B2Z9Y5), Solanum lycopersicum (B2Z9Y4), Solanum lycopersicum (B2Z9Y3), Solanum lycopersicum
brenda
Castellano, I.; Merlino, A.; Rossi, M.; La Cara, F.
Biochemical and structural properties of gamma-glutamyl transpeptidase from Geobacillus thermodenitrificans: An enzyme specialized in hydrolase activity
Biochimie
92
464-474
2010
Geobacillus thermodenitrificans
brenda
Pollard, C.; Nitz, M.; Baras, A.; Williams, P.; Moskaluk, C.; Theodorescu, D.
Genoproteomic mining of urothelial cancer suggests {gamma}-glutamyl hydrolase and diazepam-binding inhibitor as putative urinary markers of outcome after chemotherapy
Am. J. Pathol.
175
1824-1830
2009
Homo sapiens
brenda
Sadahiro, S.; Suzuki, T.; Maeda, Y.; Tanaka, A.; Ogoshi, K.; Kamijo, A.; Murayama, C.; Tsukioka, S.; Sakamoto, E.; Fukui, Y.; Oka, T.
Molecular determinants of folate levels after leucovorin administration in colorectal cancer
Cancer Chemother. Pharmacol.
65
735-742
2010
Homo sapiens (Q92820), Homo sapiens
brenda
Smit, E.F.; Burgers, S.A.; Biesma, B.; Smit, H.J.; Eppinga, P.; Dingemans, A.M.; Joerger, M.; Schellens, J.H.; Vincent, A.; van Zandwijk, N.; Groen, H.J.
Randomized phase II and pharmacogenetic study of pemetrexed compared with pemetrexed plus carboplatin in pretreated patients with advanced non-small-cell lung cancer
J. Clin. Oncol.
27
2038-2045
2009
Homo sapiens
brenda
Organista-Nava, J.; Gomez-Gomez, Y.; Saavedra-Herrera, M.V.; Rivera-Ramirez, A.B.; Teran-Porcayo, M.A.; Alarcon-Romero, L.d.e.l..C.; Illades-Aguiar, B.; Leyva-Vazquez, M.A.
Polymorphisms of the gamma-glutamyl hydrolase gene and risk of relapse to acute lymphoblastic leukemia in Mexico
Leuk. Res.
34
728-732
2010
Homo sapiens
brenda
Tsirulnikov, K.; Abuladze, N.; Bragin, A.; Faull, K.; Cascio, D.; Damoiseaux, R.; Schibler, M.J.; Pushkin, A.
Inhibition of aminoacylase 3 protects rat brain cortex neuronal cells from the toxicity of 4-hydroxy-2-nonenal mercapturate and 4-hydroxy-2-nonenal
Toxicol. Appl. Pharmacol.
263
303-314
2012
Mus musculus
brenda
Kim, S.E.; Cole, P.D.; Cho, R.C.; Ly, A.; Ishiguro, L.; Sohn, K.J.; Croxford, R.; Kamen, B.A.; Kim, Y.I.
gamma-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate
Br. J. Cancer
109
2175-2188
2013
Homo sapiens
brenda
Ramos-Parra, P.; Urrea-Lopez, R.; Diaz de la Garza, R.
Folate analysis in complex food matrices: Use of a recombinant Arabidopsis gamma-glutamyl hydrolase for folate deglutamylation
Food Res. Int.
54
177-185
2013
Arabidopsis thaliana (O65355)
-
brenda
Kim, S.E.; Hinoue, T.; Kim, M.S.; Sohn, K.J.; Cho, R.C.; Cole, P.D.; Weisenberger, D.J.; Laird, P.W.; Kim, Y.I.
gamma-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells
Genes Nutr.
10
444
2015
Homo sapiens
brenda
Chuankhayan, P.; Kao, T.T.; Lin, C.C.; Guan, H.H.; Nakagawa, A.; Fu, T.F.; Chen, C.J.
Structural insights into the hydrolysis and polymorphism of methotrexate polyglutamate by zebrafish gamma-glutamyl hydrolase
J. Med. Chem.
56
7625-7635
2013
Danio rerio (Q6NY42)
brenda
Fujimoto, Z.; Kimura, K.
Crystal structure of bacteriophage phiNIT1 zinc peptidase PghP that hydrolyzes gamma-glutamyl linkage of bacterial poly-gamma-glutamate
Proteins Struct. Funct. Bioinform.
80
722-732
2012
Bacillus phage phiNIT1 (Q852V1)
brenda
Maezawa, Y.; Sakamaki, K.; Oue, N.; Kimura, Y.; Hashimoto, I.; Hara, K.; Kano, K.; Aoyama, T.; Hiroshima, Y.; Yamada, T.; Yamamoto, N.; Ogata, T.; Ito, H.; Cho, H.; Shiozawa, M.; Yoshikawa, T.; Morinaga, S.; Rino, Y.; Yasui, W.; Masuda, M.; Miyagi, Y.; Oshima, T.
High gamma-glutamyl hydrolase and low folylpolyglutamate synthetase expression as prognostic biomarkers in patients with locally advanced gastric cancer who were administrated postoperative adjuvant chemotherapy with S-1
J. Cancer Res. Clin. Oncol.
146
75-86
2020
Homo sapiens (Q92820)
brenda
Jiang, H.; Yang, J.; Hou, Y.; Zhang, K.; Ren, Y.; Huang, J.; Li, H.; Cai, T.; Ouyang, Z.; Zhao, J.; Yu, P.
Evaluation of intracellular metabolism of methotrexate in hepatocytes and embryonic kidney cells based on folylpolyglutamate synthetase and gamma-glutamyl hydrolase expression
Curr. Drug Metab.
24
139-147
2023
Homo sapiens (Q92820)
brenda
Wang, S.; Chen, Y.; Fang, H.; Xu, Y.; Ding, M.; Ma, C.; Lin, Y.; Cui, Z.; Sun, H.; Niu, Q.; Sun, S.; Zhou, B.S.; Xiao, N.; Li, H.
A gamma-glutamyl hydrolase lacking the signal peptide confers susceptibility to folates/antifolates in acute lymphoblastic leukemia cells
FEBS Lett.
596
437-448
2022
Homo sapiens (Q92820)
brenda
Chen, Y.J.; Guo, X.; Liu, M.L.; Yu, Y.Y.; Cui, Y.H.; Shen, X.Z.; Liu, T.S.; Liang, L.
Interaction between glycolysis-cholesterol synthesis axis and tumor microenvironment reveal that gamma-glutamyl hydrolase suppresses glycolysis in colon cancer
Front. Immunol.
13
979521
2022
Homo sapiens (Q92820)
brenda
Tyagi, K.; Sunkum, A.; Rai, M.; Yadav, A.; Sircar, S.; Sreelakshmi, Y.; Sharma, R.
Seeing the unseen a trifoliate (MYB117) mutant allele fortifies folate and carotenoids in tomato fruits
Plant J.
112
38-54
2022
Solanum tuberosum
brenda
Zhu, C.; Du, Y.; Huai, Q.; Fang, N.; Xu, W.; Yang, J.; Li, X.; Zhang, Y.; Zhang, X.; Dai, H.; Li, X.; Wang, H.; Dai, Y.
The identification of gamma-glutamyl hydrolase in uterine corpus endometrial carcinoma a predictive model and machine learning
Reprod. Sci.
31
532-549
2024
Homo sapiens (Q92820)
brenda
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