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Information on EC 3.4.19.9 - folate gamma-glutamyl hydrolase and Organism(s) Rattus norvegicus and UniProt Accession Q62867
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3.4.19.9 folate gamma-glutamyl hydrolaseIUBMB 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-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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Word Map
- 3.4.19.9
- polyglutamates
- methotrexate
-
polyglutamylation
- antifolate
- casei
- monoglutamates
- pteroylpolyglutamate
- sumo
-
monoglutamylated
- 5-methyltetrahydrofolate
-
deconjugation
-
trienzyme
- pentaglutamate
- rad6
- diglutamate
-
punicic
- medicine
- analysis
The taxonomic range for the selected organisms is: Rattus norvegicus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
+
(n-1)
=
+
(n-1)
Synonyms
conjugase, gamma-glutamyl hydrolase, folate conjugase, folylpolyglutamate hydrolase, gamma-gh, leggh2, leggh3, zgammagh, leggh1, low gamma-glutamyl hydrolase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
carboxypeptidase G
-
-
-
-
conjugase
-
-
-
-
FGPH
-
-
-
-
folate conjugase
-
-
-
-
folic acid conjugase
-
-
-
-
folylpolyglutamate hydrolase
-
-
-
-
gamma-Glu-X carboxypeptidase
-
-
-
-
gamma-glutamyl hydrolase
-
-
-
-
hydrolase, gamma-glutamyl
-
-
-
-
lysosomal gamma-glutamyl carboxypeptidase
-
-
-
-
poly(gamma-glutamic acid) endohydrolase
-
-
-
-
poly(glutamic acid) hydrolase II
-
-
-
-
polyglutamate hydrolase
-
-
-
-
pteroyl-poly-gamma-glutamate hydrolase
-
-
-
-
pteroylpoly-gamma-glutamyl hydrolase
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
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
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
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.
CAS REGISTRY NUMBER
COMMENTARY
9074-87-7
not distinguishable from EC 3.4.17.11 in Chemical Abstracts
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
(4,4-difluoro)glutamyl-gamma-glutamate + H2O
(4,4-difluoro)glutamate + glutamate
-
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
-
-
?
(poly-gamma-glutamate)n + H2O
(poly-gamma-glutamate)n-1 + glutamate
-
-
-
-
?
2,4-diamino-10-methyl-pteroylglutamyl-gamma-glutamate + H2O
2,4-diamino-10-methyl-pteroate + glutamate + gamma-glutamylglutamate
4-aminobenzoyl-(4,4-difluoro)glutamyl-gamma-glutamate + H2O
4-aminobenzoyl-(4,4-difluoro)glutamate + glutamate
-
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
-
-
?
4-aminobenzoyl-penta-gamma-glutamate + H2O
4-aminobenzoylglutamate + tetra-gamma-glutamate
-
-
subsequently degraded to glutamic acid
?
methotrexate penta-gamma-glutamate + H2O
methotrexate-gamma-glutamate + tetra-gamma-glutamate
-
-
subsequently degraded to glutamic acid
?
pteroylheptaglutamate + H2O
?
-
-
pteroylmonoglutamate + hexaglutamyl peptide
?
pteroylpolyglutamate + H2O
?
-
possible contribution of biliary enzyme to intestinal absorption of folate polyglutamates
-
-
?
polyglutamyl-folate + H2O
monoglutamyl folate + glutamate
removal of the poly-gamma-glutamate chains
-
-
?
2,4-diamino-10-methyl-pteroylglutamyl-gamma-glutamate + H2O
2,4-diamino-10-methyl-pteroate + glutamate + gamma-glutamylglutamate
-
-
bile enzyme at a ratio of 5:95 and plasma enzyme at a ratio of 23:77
?
2,4-diamino-10-methyl-pteroylglutamyl-gamma-glutamate + H2O
2,4-diamino-10-methyl-pteroate + glutamate + gamma-glutamylglutamate
-
-
bile enzyme at a ratio of 5:95 and plasma enzyme at a ratio of 23:77
?
polyglutamyl-folate + H2O
monoglutamyl folate + glutamate
-
gamma-glutamyl hydrolase, not glutamate carboxypeptidase II, hydrolyzes dietary folate in rat small intestine
-
-
?
additional information
?
-
key enzyme in the metabolism of folic acid and the pharmacology of many antifolate drugs
-
-
?
additional information
?
-
-
protein-associated poly-gamma-glutamates are poor substrates
-
-
?
additional information
?
-
-
no hydrolysis of 4-amino-benzoyl-gamma-glutamate
-
-
?
additional information
?
-
-
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
-
-
?
additional information
?
-
-
either deacylation or rearrangement of the enzyme-product complex is rate-limiting in the isopeptide hydrolysis reaction
-
-
?
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
pteroylpolyglutamate + H2O
?
-
possible contribution of biliary enzyme to intestinal absorption of folate polyglutamates
-
-
?
polyglutamyl-folate + H2O
monoglutamyl folate + glutamate
-
gamma-glutamyl hydrolase, not glutamate carboxypeptidase II, hydrolyzes dietary folate in rat small intestine
-
-
?
additional information
?
-
key enzyme in the metabolism of folic acid and the pharmacology of many antifolate drugs
-
-
?
additional information
?
-
-
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
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
preincubation of the enzyme at 25 °C for 2 h is necessary to obtain maximal activity
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
Michaelis-Menten kinetics, detailed steady-state kinetics and partial pre-steady-state kinetics, stopped-flow method, overview
-
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
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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). GGH_RAT
317
0
35830
Swiss-Prot
Secretory Pathway (Reliability: 1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
nondissociating homodimer, homodimer formation is required for folding into the active conformation, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
the enzyme forms very stable dimeric complexes with the glycosylated human enzyme, overview
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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
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
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
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
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
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
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)
Schneider, E.; Ryan, T.J.
Gamma-glutamyl hydrolase and drug resistance
Clin. Chim. Acta
374
25-32
2006
Homo sapiens, Mus musculus, Rattus norvegicus
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