UniProt functional annotation for P19440



	UniProt functional annotation for P19440

UniProt code: P19440.

Organism: Homo sapiens (Human).

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

Function: Cleaves the gamma-glutamyl bond of extracellular glutathione (gamma-Glu-Cys-Gly), glutathione conjugates and other gamma-glutamyl compounds, such as leukotriene C4 (LTC4). The metabolism of glutathione by GGT1 releases free glutamate and the dipeptide cysteinyl-glycine, which is hydrolyzed to cysteine and glycine by dipeptidases. In the presence of high concentrations of dipeptides and some amino acids, can also catalyze a transpeptidation reaction, transferring the gamma- glutamyl moiety to an acceptor amino acid to form a new gamma-glutamyl compound (PubMed:17924658, PubMed:7673200, PubMed:7759490, PubMed:8095045, PubMed:8827453, PubMed:21447318). Contributes to cysteine homeostasis, glutathione homeostasis and in the conversion of the leukotriene LTC4 to LTD4. {ECO:0000269|PubMed:17924658, ECO:0000269|PubMed:20622017, ECO:0000269|PubMed:21447318, ECO:0000269|PubMed:24047895, ECO:0000269|PubMed:7673200, ECO:0000269|PubMed:7759490, ECO:0000269|PubMed:8095045, ECO:0000269|PubMed:8827453}.

Function: [Isoform 3]: Seems to be inactive. {ECO:0000269|PubMed:7689219}.

Catalytic activity: Reaction=an alpha-amino acid + an N-terminal (5-L-glutamyl)-[peptide] = 5-L-glutamyl amino acid + N-terminal L-alpha-aminoacyl-[peptide]; Xref=Rhea:RHEA:23904, Rhea:RHEA-COMP:9780, Rhea:RHEA-COMP:9795, ChEBI:CHEBI:77644, ChEBI:CHEBI:78597, ChEBI:CHEBI:78599, ChEBI:CHEBI:78608; EC=2.3.2.2; Evidence={ECO:0000269|PubMed:17924658, ECO:0000269|PubMed:21447318, ECO:0000269|PubMed:23682772, ECO:0000269|PubMed:7673200, ECO:0000269|PubMed:7759490, ECO:0000269|PubMed:8095045, ECO:0000269|PubMed:8827453};

Catalytic activity: Reaction=glutathione + H2O = L-cysteinylglycine + L-glutamate; Xref=Rhea:RHEA:28807, ChEBI:CHEBI:15377, ChEBI:CHEBI:29985, ChEBI:CHEBI:57925, ChEBI:CHEBI:61694; EC=3.4.19.13; Evidence={ECO:0000269|PubMed:17924658, ECO:0000269|PubMed:21447318}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:28808; Evidence={ECO:0000305|PubMed:21447318};

Catalytic activity: Reaction=an S-substituted glutathione + H2O = an S-substituted L- cysteinylglycine + L-glutamate; Xref=Rhea:RHEA:59468, ChEBI:CHEBI:15377, ChEBI:CHEBI:29985, ChEBI:CHEBI:90779, ChEBI:CHEBI:143103; EC=3.4.19.13; Evidence={ECO:0000269|PubMed:17924658, ECO:0000269|PubMed:21447318}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59469; Evidence={ECO:0000305|PubMed:21447318};

Catalytic activity: Reaction=H2O + leukotriene C4 = L-glutamate + leukotriene D4; Xref=Rhea:RHEA:31563, ChEBI:CHEBI:15377, ChEBI:CHEBI:29985, ChEBI:CHEBI:57973, ChEBI:CHEBI:63166; EC=3.4.19.14; Evidence={ECO:0000269|PubMed:21447318}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:31564; Evidence={ECO:0000305};

Activity regulation: Activated by autocatalytic cleavage (PubMed:23682772). Inhibited by serine-borate (PubMed:21447318). {ECO:0000269|PubMed:21447318, ECO:0000269|PubMed:23682772}.

Biophysicochemical properties: Kinetic parameters: KM=11 mM for glycylglycine {ECO:0000269|PubMed:7759490}; KM=10.6 uM for glutathione {ECO:0000269|PubMed:21447318}; KM=8.8 uM for oxidized-glutathione {ECO:0000269|PubMed:21447318}; KM=1.3 mM for D-gamma-glutamyl-p-nitroanalide {ECO:0000269|PubMed:7759490}; KM=9.9 uM for S-methylglutathion {ECO:0000269|PubMed:21447318}; KM=33.4 uM for gamma-glutamyl leucine {ECO:0000269|PubMed:21447318}; KM=10.8 uM for leukotriene C4 {ECO:0000269|PubMed:21447318};

Pathway: Lipid metabolism; leukotriene D4 biosynthesis. {ECO:0000269|PubMed:21447318}.

Pathway: Sulfur metabolism; glutathione metabolism. {ECO:0000269|PubMed:21447318}.

Subunit: Heterodimer composed of the light and heavy chains. The active site is located in the light chain. {ECO:0000269|PubMed:24047895, ECO:0000269|PubMed:8095045}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:23682772, ECO:0000269|PubMed:8095045}; Single-pass type II membrane protein {ECO:0000250|UniProtKB:P07314}.

Tissue specificity: Detected in fetal and adult kidney and liver, adult pancreas, stomach, intestine, placenta and lung. There are several other tissue-specific forms that arise from alternative promoter usage but that produce the same protein.

Tissue specificity: [Isoform 3]: Lung-specific. {ECO:0000269|PubMed:7689219}.

Ptm: N-glycosylated on both chains. Contains hexoses, hexosamines and sialic acid residues. Glycosylation profiles tested in kidney and liver tissues reveal the presence of tissue-specific and site-specific glycan composition, despite the overlap in composition among the N-glycans. A total of 36 glycan compositions, with 40 unique structures are observed. Up to 15 different glycans are observed at a single site, with site-specific variation in glycan composition. The difference in glycosylation profiles in the 2 tissues do not affect the enzyme activity. {ECO:0000269|PubMed:15084671, ECO:0000269|PubMed:17924658, ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19349973, ECO:0000269|PubMed:19463, ECO:0000269|PubMed:20622017, ECO:0000269|PubMed:23682772, ECO:0000269|PubMed:24047895, ECO:0000269|PubMed:2900635}.

Ptm: Cleaved by autocatalysis into a large and a small subunit and the autocatalytic cleavage is essential to the functional activation of the enzyme. {ECO:0000269|PubMed:23682772}.

Disease: Glutathionuria (GLUTH) [MIM:231950]: A very rare, autosomal recessive metabolic disorder characterized by the presence of glutathione in the urine, due to generalized gamma-glutamyl transpeptidase deficiency. Most patients manifest mild to moderate mental retardation, and behavioral disturbance. Seizures, tremor, marfanoid features and strabismus are observed in some patients. {ECO:0000269|PubMed:29483667}. Note=The disease is caused by variants affecting the gene represented in this entry. A large homozygous deletion that removes several exons of all isoforms of GGT1 has been found in one family affected by glutathionuria. {ECO:0000269|PubMed:29483667}.

Miscellaneous: Cys-454 was thought to bind the gamma-glutamyl moiety, but mutagenesis of this residue had no effect on activity. {ECO:0000269|PubMed:7759490}.

Miscellaneous: Chloride ions bound in the active site cavity may contribute to stabilize the protein fold. {ECO:0000305|PubMed:24047895}.

Miscellaneous: [Isoform 1]: Produced by alternative promoter usage.

Miscellaneous: [Isoform 2]: Produced by alternative splicing of isoform 1. {ECO:0000305}.

Miscellaneous: [Isoform 3]: Produced by alternative promoter usage. {ECO:0000305}.

Similarity: Belongs to the gamma-glutamyltransferase family. {ECO:0000305}.

Sequence caution: Sequence=AAA35899.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={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:		Cleaves the gamma-glutamyl bond of extracellular glutathione (gamma-Glu-Cys-Gly), glutathione conjugates and other gamma-glutamyl compounds, such as leukotriene C4 (LTC4). The metabolism of glutathione by GGT1 releases free glutamate and the dipeptide cysteinyl-glycine, which is hydrolyzed to cysteine and glycine by dipeptidases. In the presence of high concentrations of dipeptides and some amino acids, can also catalyze a transpeptidation reaction, transferring the gamma- glutamyl moiety to an acceptor amino acid to form a new gamma-glutamyl compound (PubMed:17924658, PubMed:7673200, PubMed:7759490, PubMed:8095045, PubMed:8827453, PubMed:21447318). Contributes to cysteine homeostasis, glutathione homeostasis and in the conversion of the leukotriene LTC4 to LTD4. {ECO:0000269\|PubMed:17924658, ECO:0000269\|PubMed:20622017, ECO:0000269\|PubMed:21447318, ECO:0000269\|PubMed:24047895, ECO:0000269\|PubMed:7673200, ECO:0000269\|PubMed:7759490, ECO:0000269\|PubMed:8095045, ECO:0000269\|PubMed:8827453}.



Function:		[Isoform 3]: Seems to be inactive. {ECO:0000269\|PubMed:7689219}.


Catalytic activity:		Reaction=an alpha-amino acid + an N-terminal (5-L-glutamyl)-[peptide] = 5-L-glutamyl amino acid + N-terminal L-alpha-aminoacyl-[peptide]; Xref=Rhea:RHEA:23904, Rhea:RHEA-COMP:9780, Rhea:RHEA-COMP:9795, ChEBI:CHEBI:77644, ChEBI:CHEBI:78597, ChEBI:CHEBI:78599, ChEBI:CHEBI:78608; EC=2.3.2.2; Evidence={ECO:0000269\|PubMed:17924658, ECO:0000269\|PubMed:21447318, ECO:0000269\|PubMed:23682772, ECO:0000269\|PubMed:7673200, ECO:0000269\|PubMed:7759490, ECO:0000269\|PubMed:8095045, ECO:0000269\|PubMed:8827453};
Catalytic activity:		Reaction=glutathione + H2O = L-cysteinylglycine + L-glutamate; Xref=Rhea:RHEA:28807, ChEBI:CHEBI:15377, ChEBI:CHEBI:29985, ChEBI:CHEBI:57925, ChEBI:CHEBI:61694; EC=3.4.19.13; Evidence={ECO:0000269\|PubMed:17924658, ECO:0000269\|PubMed:21447318}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:28808; Evidence={ECO:0000305\|PubMed:21447318};
Catalytic activity:		Reaction=an S-substituted glutathione + H2O = an S-substituted L- cysteinylglycine + L-glutamate; Xref=Rhea:RHEA:59468, ChEBI:CHEBI:15377, ChEBI:CHEBI:29985, ChEBI:CHEBI:90779, ChEBI:CHEBI:143103; EC=3.4.19.13; Evidence={ECO:0000269\|PubMed:17924658, ECO:0000269\|PubMed:21447318}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59469; Evidence={ECO:0000305\|PubMed:21447318};
Catalytic activity:		Reaction=H2O + leukotriene C4 = L-glutamate + leukotriene D4; Xref=Rhea:RHEA:31563, ChEBI:CHEBI:15377, ChEBI:CHEBI:29985, ChEBI:CHEBI:57973, ChEBI:CHEBI:63166; EC=3.4.19.14; Evidence={ECO:0000269\|PubMed:21447318}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:31564; Evidence={ECO:0000305};
Activity regulation:		Activated by autocatalytic cleavage (PubMed:23682772). Inhibited by serine-borate (PubMed:21447318). {ECO:0000269\|PubMed:21447318, ECO:0000269\|PubMed:23682772}.
Biophysicochemical properties:		Kinetic parameters: KM=11 mM for glycylglycine {ECO:0000269\|PubMed:7759490}; KM=10.6 uM for glutathione {ECO:0000269\|PubMed:21447318}; KM=8.8 uM for oxidized-glutathione {ECO:0000269\|PubMed:21447318}; KM=1.3 mM for D-gamma-glutamyl-p-nitroanalide {ECO:0000269\|PubMed:7759490}; KM=9.9 uM for S-methylglutathion {ECO:0000269\|PubMed:21447318}; KM=33.4 uM for gamma-glutamyl leucine {ECO:0000269\|PubMed:21447318}; KM=10.8 uM for leukotriene C4 {ECO:0000269\|PubMed:21447318};
Pathway:		Lipid metabolism; leukotriene D4 biosynthesis. {ECO:0000269\|PubMed:21447318}.
Pathway:		Sulfur metabolism; glutathione metabolism. {ECO:0000269\|PubMed:21447318}.
Subunit:		Heterodimer composed of the light and heavy chains. The active site is located in the light chain. {ECO:0000269\|PubMed:24047895, ECO:0000269\|PubMed:8095045}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:23682772, ECO:0000269\|PubMed:8095045}; Single-pass type II membrane protein {ECO:0000250\|UniProtKB:P07314}.
Tissue specificity:		Detected in fetal and adult kidney and liver, adult pancreas, stomach, intestine, placenta and lung. There are several other tissue-specific forms that arise from alternative promoter usage but that produce the same protein.
Tissue specificity:		[Isoform 3]: Lung-specific. {ECO:0000269\|PubMed:7689219}.
Ptm:		N-glycosylated on both chains. Contains hexoses, hexosamines and sialic acid residues. Glycosylation profiles tested in kidney and liver tissues reveal the presence of tissue-specific and site-specific glycan composition, despite the overlap in composition among the N-glycans. A total of 36 glycan compositions, with 40 unique structures are observed. Up to 15 different glycans are observed at a single site, with site-specific variation in glycan composition. The difference in glycosylation profiles in the 2 tissues do not affect the enzyme activity. {ECO:0000269\|PubMed:15084671, ECO:0000269\|PubMed:17924658, ECO:0000269\|PubMed:19159218, ECO:0000269\|PubMed:19349973, ECO:0000269\|PubMed:19463, ECO:0000269\|PubMed:20622017, ECO:0000269\|PubMed:23682772, ECO:0000269\|PubMed:24047895, ECO:0000269\|PubMed:2900635}.
Ptm:		Cleaved by autocatalysis into a large and a small subunit and the autocatalytic cleavage is essential to the functional activation of the enzyme. {ECO:0000269\|PubMed:23682772}.
Disease:		Glutathionuria (GLUTH) [MIM:231950]: A very rare, autosomal recessive metabolic disorder characterized by the presence of glutathione in the urine, due to generalized gamma-glutamyl transpeptidase deficiency. Most patients manifest mild to moderate mental retardation, and behavioral disturbance. Seizures, tremor, marfanoid features and strabismus are observed in some patients. {ECO:0000269\|PubMed:29483667}. Note=The disease is caused by variants affecting the gene represented in this entry. A large homozygous deletion that removes several exons of all isoforms of GGT1 has been found in one family affected by glutathionuria. {ECO:0000269\|PubMed:29483667}.
Miscellaneous:		Cys-454 was thought to bind the gamma-glutamyl moiety, but mutagenesis of this residue had no effect on activity. {ECO:0000269\|PubMed:7759490}.
Miscellaneous:		Chloride ions bound in the active site cavity may contribute to stabilize the protein fold. {ECO:0000305\|PubMed:24047895}.
Miscellaneous:		[Isoform 1]: Produced by alternative promoter usage.
Miscellaneous:		[Isoform 2]: Produced by alternative splicing of isoform 1. {ECO:0000305}.
Miscellaneous:		[Isoform 3]: Produced by alternative promoter usage. {ECO:0000305}.
Similarity:		Belongs to the gamma-glutamyltransferase family. {ECO:0000305}.
Sequence caution:		Sequence=AAA35899.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};