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Catalytic Site Atlas

CSA LITERATURE entry for 1h19

E.C. nameleukotriene-A4 hydrolase
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz) 3.3.2.6
CSA Homologues of 1h19There are 56 Homologs
CSA Entries With UniProtID P09960
CSA Entries With EC Number 3.3.2.6
PDBe Entry 1h19
PDBSum Entry 1h19
MACiE Entry M0166

Literature Report

IntroductionLeukotriene A4 hydrolase/ Aminopeptidase is involved in the immune response in humans, and is unique in its ability to catalyse two very different reactions at the active site. Not only is it able to catalyse the hydrolysis of the epoxide Leukotriene A4 to produce the potent immune activator Leukotriene B4, it is also able to catalyse the hydrolysis of peptide bonds, acting on the first peptide bond after the N terminal. One active site is enough to confer such variety of function, so the enzyme represents a yardstick of evolutionary efficiency seldom reached in nature. It displays a characteristic Zinc binding motif at the active site (GXMEN) which places it in the family M1 of Zinc metalloproteases.
MechansimIn the hydrolysis of Leukotriene, a water molecule, activated by Zinc acts as an acid to protonate the epoxide, causing ring opening. This leads to a carbocation, stabilised by delocalisation between the three double bonds. Nucleophilic attack by the OH- ion, activated this time by Glu 271, on the terminal double bond of the delocalised system leads to the final product Leukotriene B4. In the hydrolysis of peptides, a water molecule, activated by Glu 296 and Zinc, attacks the peptide bond leading to a tetrahedral intermediate with negative charge localised to the oxygen. This is stabilised by binding to Zn2+ and by favourable contacts between the N terminal section and Glu 271. Protonation of the leaving group by Tyr 383 leads to collapse of the intermediate and the formation of the products.
Reaction

Catalytic Sites for 1h19

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
TyrA383384macie:sideChainProtonates the leaving group thus allowing collapse of the tetrahedral intermediate to occur.
GluA296297macie:sideChainActivates a water molecule for nucleophilic attack by deprotonation; thus is a general base for the reaction.
GlnA271272macie:sideChainHas a vital role in both mechanisms. In the hydrolysis of the epoxide, acts to activate a water molecule towards nucleophilic attack. In the hydrolysis of the aminopeptide, acts to stabilise the tetrahedral intermediate by contact with the amino terminal.

Literature References

Notes:
Rudberg PC
Leukotriene A4 hydrolase/aminopeptidase. Glutamate 271 is a catalytic residue with specific roles in two distinct enzyme mechanisms.
J Biol Chem 2002 277 1398-1404
PubMed: 11675384
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