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Search The CSA
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Catalytic Site Atlas

CSA LITERATURE entry for 1l9x

E.C. namegamma-glutamyl hydrolase
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz) 3.4.19.9
CSA Homologues of 1l9x
CSA Entries With UniProtID Q92820
CSA Entries With EC Number 3.4.19.9
PDBe Entry 1l9x
PDBSum Entry 1l9x
MACiE Entry 1l9x

Literature Report

Introductiongamma-glutamyl hydrolase is a lysosomal or secreted thiol-dependent peptidase most active at acidic pH that catalyses the cleavage of the gamma-glutamyl chain of folylpoly-gamma-glutamyl. Human gamma-glutamyl hydrolase (hGH) catalyses the hydrolysis of the gamma-linked polyglutamate chain of folyl- or antifolyl polyglutamates, releasing shorter chains of polyglutamates and diglutamates or glutamic acid.
MechansimHis220 activates Cys110 by abstracting a proton. The nucleophilic Cys110 attacks the gamma-carbonyl carbon of the of the susceptible Glu-Glu bond in the poly-gamma-glutamate substrate, forming a tetrahedral intermediate with an oxyanion. The carbonyl C-N bond is cleaved, forming the thioester intermediate and the gamma-linked glutamate leaving group which is protonated by His220. The thioester intermediate is hydrolysed by a water molecule which is activated by His220 acting as a base, yielding the product and regenerating the enzyme.
Reaction

Catalytic Sites for 1l9x

Annotated By Reference To The Literature - Site 5 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisA220244macie:sideChainHis220 acts as a general acid/base catalyst. It activates the two nucleophiles in the reaction (Cys110 and water) as a base, and protonates the leaving group.
CysA110134macie:sideChainActivated Cys110 nucleophilically attacks the gamma-carbonyl carbon of the substrate to form the thioester intermediate.

Annotated By Reference To The Literature - Site 6 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisB220244macie:sideChainHis220 acts as a general acid/base catalyst. It activates the two nucleophiles in the reaction (Cys110 and water) as a base, and protonates the leaving group.
CysB110134macie:sideChainActivated Cys110 nucleophilically attacks the gamma-carbonyl carbon of the substrate to form the thioester intermediate.

Annotated By Reference To The Literature - Site 7 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisC220244macie:sideChainHis220 acts as a general acid/base catalyst. It activates the two nucleophiles in the reaction (Cys110 and water) as a base, and protonates the leaving group.
CysC110134macie:sideChainActivated Cys110 nucleophilically attacks the gamma-carbonyl carbon of the substrate to form the thioester intermediate.

Annotated By Reference To The Literature - Site 8 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
HisD220244macie:sideChainHis220 acts as a general acid/base catalyst. It activates the two nucleophiles in the reaction (Cys110 and water) as a base, and protonates the leaving group.
CysD110134macie:sideChainActivated Cys110 nucleophilically attacks the gamma-carbonyl carbon of the substrate to form the thioester intermediate.

Literature References

Notes:Mechanism is generally based on E. coli homologue.
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