UniProt functional annotation for P09960



	UniProt functional annotation for P09960

UniProt code: P09960.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Bifunctional zinc metalloenzyme that comprises both epoxide hydrolase (EH) and aminopeptidase activities. Acts as an epoxide hydrolase to catalyze the conversion of LTA4 to the proinflammatory mediator leukotriene B4 (LTB4) (PubMed:11917124, PubMed:12207002, PubMed:15078870, PubMed:18804029, PubMed:1897988, PubMed:1975494, PubMed:2244921). Has also aminopeptidase activity, with high affinity for N-terminal arginines of various synthetic tripeptides (PubMed:20813919, PubMed:18804029). In addition to its proinflammatory EH activity, may also counteract inflammation by its aminopeptidase activity, which inactivates by cleavage another neutrophil attractant, the tripeptide Pro-Gly-Pro (PGP), a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP9) and prolylendopeptidase (PREPL) (PubMed:20813919, PubMed:24591641). Involved also in the biosynthesis of resolvin E1 and 18S-resolvin E1 from eicosapentaenoic acid, two lipid mediators that show potent anti- inflammatory and pro-resolving actions (PubMed:21206090). {ECO:0000269|PubMed:11917124, ECO:0000269|PubMed:12207002, ECO:0000269|PubMed:15078870, ECO:0000269|PubMed:18804029, ECO:0000269|PubMed:1897988, ECO:0000269|PubMed:1975494, ECO:0000269|PubMed:20813919, ECO:0000269|PubMed:21206090, ECO:0000269|PubMed:2244921, ECO:0000269|PubMed:24591641}.

Catalytic activity: Reaction=H2O + leukotriene A4 = leukotriene B4; Xref=Rhea:RHEA:22324, ChEBI:CHEBI:15377, ChEBI:CHEBI:57461, ChEBI:CHEBI:57463; EC=3.3.2.6; Evidence={ECO:0000269|PubMed:11675384, ECO:0000269|PubMed:11917124, ECO:0000269|PubMed:12207002, ECO:0000269|PubMed:15078870, ECO:0000269|PubMed:18804029, ECO:0000269|PubMed:1897988, ECO:0000269|PubMed:24591641, ECO:0000269|PubMed:6490615, ECO:0000269|PubMed:7667299, ECO:0000269|PubMed:9395533}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22325; Evidence={ECO:0000305|PubMed:11917124};

Catalytic activity: Reaction=(5S,6S)-epoxy-(18R)-hydroxy-(7E,9E,11Z,14Z,16E)- eicosapentaenoate + H2O = resolvin E1; Xref=Rhea:RHEA:50272, ChEBI:CHEBI:15377, ChEBI:CHEBI:91000, ChEBI:CHEBI:132219; Evidence={ECO:0000269|PubMed:21206090}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50273; Evidence={ECO:0000305|PubMed:21206090};

Catalytic activity: Reaction=(5S,6S)-epoxy-(18S)-hydroxy-(7E,9E,11Z,14Z,16E)- eicosapentaenoate + H2O = 18S-resolvin E1; Xref=Rhea:RHEA:51988, ChEBI:CHEBI:15377, ChEBI:CHEBI:134661, ChEBI:CHEBI:136057; Evidence={ECO:0000269|PubMed:21206090}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:51989; Evidence={ECO:0000305|PubMed:21206090};

Catalytic activity: Reaction=Release of the N-terminal residue from a tripeptide.; EC=3.4.11.4; Evidence={ECO:0000269|PubMed:11675384, ECO:0000269|PubMed:11917124, ECO:0000269|PubMed:20813919, ECO:0000269|PubMed:24591641, ECO:0000269|PubMed:9395533};

Cofactor: Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:11175901, ECO:0000269|PubMed:12207002, ECO:0000269|PubMed:15078870, ECO:0000269|PubMed:18804029, ECO:0000269|PubMed:24591641}; Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:12207002, ECO:0000269|PubMed:15078870, ECO:0000269|PubMed:18804029};

Activity regulation: Inhibited by bestatin (PubMed:11175901). The epoxide hydrolase activity is restrained by suicide inactivation that involves binding of LTA4 to Tyr-379 (PubMed:7667299). 4-(4- benzylphenyl)thiazol-2-amine (ARM1) selectively inhibits the epoxide hydrolase activity (PubMed:24591641). {ECO:0000269|PubMed:11175901, ECO:0000269|PubMed:24591641, ECO:0000269|PubMed:7667299}.

Biophysicochemical properties: Kinetic parameters: KM=1.29 mM for Pro-Gly-Pro {ECO:0000269|PubMed:20813919};

Pathway: Lipid metabolism; leukotriene B4 biosynthesis. {ECO:0000269|PubMed:11917124}.

Subunit: Monomer. {ECO:0000269|PubMed:11917124, ECO:0000269|PubMed:12207002, ECO:0000269|PubMed:15078870}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:6490615}.

Tissue specificity: Isoform 1 and isoform 2 are expressed in monocytes, lymphocytes, neutrophils, reticulocytes, platelets and fibroblasts.

Ptm: Phosphorylation at Ser-416 inhibits leukotriene-A4 hydrolase activity. {ECO:0000269|PubMed:9395533}.

Similarity: Belongs to the peptidase M1 family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Bifunctional zinc metalloenzyme that comprises both epoxide hydrolase (EH) and aminopeptidase activities. Acts as an epoxide hydrolase to catalyze the conversion of LTA4 to the proinflammatory mediator leukotriene B4 (LTB4) (PubMed:11917124, PubMed:12207002, PubMed:15078870, PubMed:18804029, PubMed:1897988, PubMed:1975494, PubMed:2244921). Has also aminopeptidase activity, with high affinity for N-terminal arginines of various synthetic tripeptides (PubMed:20813919, PubMed:18804029). In addition to its proinflammatory EH activity, may also counteract inflammation by its aminopeptidase activity, which inactivates by cleavage another neutrophil attractant, the tripeptide Pro-Gly-Pro (PGP), a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP9) and prolylendopeptidase (PREPL) (PubMed:20813919, PubMed:24591641). Involved also in the biosynthesis of resolvin E1 and 18S-resolvin E1 from eicosapentaenoic acid, two lipid mediators that show potent anti- inflammatory and pro-resolving actions (PubMed:21206090). {ECO:0000269\|PubMed:11917124, ECO:0000269\|PubMed:12207002, ECO:0000269\|PubMed:15078870, ECO:0000269\|PubMed:18804029, ECO:0000269\|PubMed:1897988, ECO:0000269\|PubMed:1975494, ECO:0000269\|PubMed:20813919, ECO:0000269\|PubMed:21206090, ECO:0000269\|PubMed:2244921, ECO:0000269\|PubMed:24591641}.


Catalytic activity:		Reaction=H2O + leukotriene A4 = leukotriene B4; Xref=Rhea:RHEA:22324, ChEBI:CHEBI:15377, ChEBI:CHEBI:57461, ChEBI:CHEBI:57463; EC=3.3.2.6; Evidence={ECO:0000269\|PubMed:11675384, ECO:0000269\|PubMed:11917124, ECO:0000269\|PubMed:12207002, ECO:0000269\|PubMed:15078870, ECO:0000269\|PubMed:18804029, ECO:0000269\|PubMed:1897988, ECO:0000269\|PubMed:24591641, ECO:0000269\|PubMed:6490615, ECO:0000269\|PubMed:7667299, ECO:0000269\|PubMed:9395533}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22325; Evidence={ECO:0000305\|PubMed:11917124};
Catalytic activity:		Reaction=(5S,6S)-epoxy-(18R)-hydroxy-(7E,9E,11Z,14Z,16E)- eicosapentaenoate + H2O = resolvin E1; Xref=Rhea:RHEA:50272, ChEBI:CHEBI:15377, ChEBI:CHEBI:91000, ChEBI:CHEBI:132219; Evidence={ECO:0000269\|PubMed:21206090}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50273; Evidence={ECO:0000305\|PubMed:21206090};
Catalytic activity:		Reaction=(5S,6S)-epoxy-(18S)-hydroxy-(7E,9E,11Z,14Z,16E)- eicosapentaenoate + H2O = 18S-resolvin E1; Xref=Rhea:RHEA:51988, ChEBI:CHEBI:15377, ChEBI:CHEBI:134661, ChEBI:CHEBI:136057; Evidence={ECO:0000269\|PubMed:21206090}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:51989; Evidence={ECO:0000305\|PubMed:21206090};
Catalytic activity:		Reaction=Release of the N-terminal residue from a tripeptide.; EC=3.4.11.4; Evidence={ECO:0000269\|PubMed:11675384, ECO:0000269\|PubMed:11917124, ECO:0000269\|PubMed:20813919, ECO:0000269\|PubMed:24591641, ECO:0000269\|PubMed:9395533};
Cofactor:		Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269\|PubMed:11175901, ECO:0000269\|PubMed:12207002, ECO:0000269\|PubMed:15078870, ECO:0000269\|PubMed:18804029, ECO:0000269\|PubMed:24591641}; Note=Binds 1 zinc ion per subunit. {ECO:0000269\|PubMed:12207002, ECO:0000269\|PubMed:15078870, ECO:0000269\|PubMed:18804029};
Activity regulation:		Inhibited by bestatin (PubMed:11175901). The epoxide hydrolase activity is restrained by suicide inactivation that involves binding of LTA4 to Tyr-379 (PubMed:7667299). 4-(4- benzylphenyl)thiazol-2-amine (ARM1) selectively inhibits the epoxide hydrolase activity (PubMed:24591641). {ECO:0000269\|PubMed:11175901, ECO:0000269\|PubMed:24591641, ECO:0000269\|PubMed:7667299}.
Biophysicochemical properties:		Kinetic parameters: KM=1.29 mM for Pro-Gly-Pro {ECO:0000269\|PubMed:20813919};
Pathway:		Lipid metabolism; leukotriene B4 biosynthesis. {ECO:0000269\|PubMed:11917124}.
Subunit:		Monomer. {ECO:0000269\|PubMed:11917124, ECO:0000269\|PubMed:12207002, ECO:0000269\|PubMed:15078870}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:6490615}.
Tissue specificity:		Isoform 1 and isoform 2 are expressed in monocytes, lymphocytes, neutrophils, reticulocytes, platelets and fibroblasts.
Ptm:		Phosphorylation at Ser-416 inhibits leukotriene-A4 hydrolase activity. {ECO:0000269\|PubMed:9395533}.
Similarity:		Belongs to the peptidase M1 family. {ECO:0000305}.