UniProt functional annotation for O94925



	UniProt functional annotation for O94925

UniProt code: O94925.

Organism: Homo sapiens (Human).

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

Function: Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate, the main excitatory neurotransmitter in the brain (PubMed:30575854, PubMed:30239721, PubMed:30970188). {ECO:0000269|PubMed:30239721, ECO:0000269|PubMed:30575854, ECO:0000269|PubMed:30970188}.

Function: [Isoform 2]: Lacks catalytic activity. {ECO:0000269|PubMed:11015561}.

Catalytic activity: Reaction=H2O + L-glutamine = L-glutamate + NH4(+); Xref=Rhea:RHEA:15889, ChEBI:CHEBI:15377, ChEBI:CHEBI:28938, ChEBI:CHEBI:29985, ChEBI:CHEBI:58359; EC=3.5.1.2; Evidence={ECO:0000269|PubMed:22049910, ECO:0000269|PubMed:22538822, ECO:0000269|PubMed:24451979, ECO:0000269|PubMed:26988803, ECO:0000269|PubMed:28526749, ECO:0000269|PubMed:29317493};

Activity regulation: Isoform 1 and isoform 3 are activated by phosphate. Inhibited by BPTES. BPTES binds between subunits and favors dissociation of the tetramer into dimers (PubMed:22049910). Inhibited by 6-diazo-5-oxo-L-norleucine (DON) (PubMed:24451979). Enzyme activity is stimulated by phosphorylation (PubMed:22538822). {ECO:0000269|PubMed:22049910, ECO:0000269|PubMed:22538822, ECO:0000269|PubMed:24451979}.

Biophysicochemical properties: Kinetic parameters: KM=1.9 mM for glutamine (isoform 1) {ECO:0000269|PubMed:22049910}; KM=1.4 mM for glutamine (isoform 3) {ECO:0000269|PubMed:22049910};

Subunit: Homotetramer, dimer of dimers (PubMed:22538822, PubMed:26988803, PubMed:28526749, PubMed:29317493). The tetramers can assemble into rod-like oligomers (in vitro), but the physiological significance of this is not clear (By similarity). Interacts with RAF1 and MAP2K2 (PubMed:22538822). Interacts with ATCAY; the interaction is direct and may control GLS localization, negatively regulating its activity. {ECO:0000250|UniProtKB:D3Z7P3, ECO:0000269|PubMed:16899818, ECO:0000269|PubMed:22049910, ECO:0000269|PubMed:22538822, ECO:0000269|PubMed:26988803, ECO:0000269|PubMed:28526749, ECO:0000269|PubMed:29317493}.

Subcellular location: [Isoform 1]: Mitochondrion {ECO:0000250|UniProtKB:P13264}. Cytoplasm, cytosol {ECO:0000269|PubMed:22228304}. Note=The 74-kDa cytosolic precursor is translocated into the mitochondria and processed via a 72-kDa intermediate to yield the mature 68- and 65-kDa subunits. {ECO:0000250|UniProtKB:P13264}.

Subcellular location: [Isoform 3]: Mitochondrion {ECO:0000269|PubMed:22228304}.

Subcellular location: [Glutaminase kidney isoform, mitochondrial 68 kDa chain]: Mitochondrion matrix {ECO:0000250|UniProtKB:P13264}. Note=Produced by the proteolytic processing of the 74-kDa cytosolic precursor. {ECO:0000250|UniProtKB:P13264}.

Subcellular location: [Glutaminase kidney isoform, mitochondrial 65 kDa chain]: Mitochondrion matrix {ECO:0000250|UniProtKB:P13264}. Note=Produced by the proteolytic processing of the 74-kDa cytosolic precursor. {ECO:0000250|UniProtKB:P13264}.

Tissue specificity: Isoform 1 and isoform 3 are detected in brain cortex. Isoform 3 is highly expressed in astrocytoma, ganglioglioma and ependymoma. Isoform 1 is highly expressed in brain and kidney, but not detected in liver. Isoform 3 is highly expressed in heart and pancreas, detected at lower levels in placenta, lung, pancreas and kidney, but is not detected in liver. Isoform 2 is expressed in cardiac and skeletal muscle. {ECO:0000269|PubMed:11015561}.

Domain: The C-terminal ANK repeats prevent the assembly of the supra- tetrameric filaments. {ECO:0000269|PubMed:28526749}.

Domain: A highly mobile activation loop at the dimer-dimer interface is important for enzyme activity. {ECO:0000250|UniProtKB:D3Z7P3}.

Ptm: Synthesized as a 74-kDa cytosolic precursor which is proteolytically processed by the mitochondrial-processing peptidase (MPP) via a 72-kDa intermediate to yield the mature mitochondrial 68- and 65-kDa subunits. {ECO:0000250|UniProtKB:P13264}.

Disease: Developmental and epileptic encephalopathy 71 (DEE71) [MIM:618328]: A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE71 is an autosomal recessive form with onset at birth. Death occurs in first weeks of life. {ECO:0000269|PubMed:30575854}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development (CASGID) [MIM:618339]: An autosomal dominant disease characterized by infantile-onset cataract, erythematic subcutaneous nodules, profound developmental delay, self-injurious behavior, and intracerebral glutamate excess. Histopathologic analysis of skin lesions show deep perivascular and periglandular lymphohistiocytic infiltrates and pronounced leukocytoclasia at the surface of the dermis, focal vacuolar alterations, hyperkeratosis, and parakeratosis of the epidermis. {ECO:0000269|PubMed:30239721}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Global developmental delay, progressive ataxia, and elevated glutamine (GDPAG) [MIM:618412]: An autosomal recessive disease characterized by early-onset delay in motor skills, delayed speech, progressive ataxia, and neurologic deterioration. Plasma glutamine is persistently elevated by a factor of 2.5 despite normal plasma ammonia levels. {ECO:0000269|PubMed:30970188}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the glutaminase family. {ECO:0000305}.

Sequence caution: Sequence=BAA74861.2; 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:		Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate, the main excitatory neurotransmitter in the brain (PubMed:30575854, PubMed:30239721, PubMed:30970188). {ECO:0000269\|PubMed:30239721, ECO:0000269\|PubMed:30575854, ECO:0000269\|PubMed:30970188}.



Function:		[Isoform 2]: Lacks catalytic activity. {ECO:0000269\|PubMed:11015561}.


Catalytic activity:		Reaction=H2O + L-glutamine = L-glutamate + NH4(+); Xref=Rhea:RHEA:15889, ChEBI:CHEBI:15377, ChEBI:CHEBI:28938, ChEBI:CHEBI:29985, ChEBI:CHEBI:58359; EC=3.5.1.2; Evidence={ECO:0000269\|PubMed:22049910, ECO:0000269\|PubMed:22538822, ECO:0000269\|PubMed:24451979, ECO:0000269\|PubMed:26988803, ECO:0000269\|PubMed:28526749, ECO:0000269\|PubMed:29317493};
Activity regulation:		Isoform 1 and isoform 3 are activated by phosphate. Inhibited by BPTES. BPTES binds between subunits and favors dissociation of the tetramer into dimers (PubMed:22049910). Inhibited by 6-diazo-5-oxo-L-norleucine (DON) (PubMed:24451979). Enzyme activity is stimulated by phosphorylation (PubMed:22538822). {ECO:0000269\|PubMed:22049910, ECO:0000269\|PubMed:22538822, ECO:0000269\|PubMed:24451979}.
Biophysicochemical properties:		Kinetic parameters: KM=1.9 mM for glutamine (isoform 1) {ECO:0000269\|PubMed:22049910}; KM=1.4 mM for glutamine (isoform 3) {ECO:0000269\|PubMed:22049910};
Subunit:		Homotetramer, dimer of dimers (PubMed:22538822, PubMed:26988803, PubMed:28526749, PubMed:29317493). The tetramers can assemble into rod-like oligomers (in vitro), but the physiological significance of this is not clear (By similarity). Interacts with RAF1 and MAP2K2 (PubMed:22538822). Interacts with ATCAY; the interaction is direct and may control GLS localization, negatively regulating its activity. {ECO:0000250\|UniProtKB:D3Z7P3, ECO:0000269\|PubMed:16899818, ECO:0000269\|PubMed:22049910, ECO:0000269\|PubMed:22538822, ECO:0000269\|PubMed:26988803, ECO:0000269\|PubMed:28526749, ECO:0000269\|PubMed:29317493}.
Subcellular location:		[Isoform 1]: Mitochondrion {ECO:0000250\|UniProtKB:P13264}. Cytoplasm, cytosol {ECO:0000269\|PubMed:22228304}. Note=The 74-kDa cytosolic precursor is translocated into the mitochondria and processed via a 72-kDa intermediate to yield the mature 68- and 65-kDa subunits. {ECO:0000250\|UniProtKB:P13264}.
Subcellular location:		[Isoform 3]: Mitochondrion {ECO:0000269\|PubMed:22228304}.
Subcellular location:		[Glutaminase kidney isoform, mitochondrial 68 kDa chain]: Mitochondrion matrix {ECO:0000250\|UniProtKB:P13264}. Note=Produced by the proteolytic processing of the 74-kDa cytosolic precursor. {ECO:0000250\|UniProtKB:P13264}.
Subcellular location:		[Glutaminase kidney isoform, mitochondrial 65 kDa chain]: Mitochondrion matrix {ECO:0000250\|UniProtKB:P13264}. Note=Produced by the proteolytic processing of the 74-kDa cytosolic precursor. {ECO:0000250\|UniProtKB:P13264}.
Tissue specificity:		Isoform 1 and isoform 3 are detected in brain cortex. Isoform 3 is highly expressed in astrocytoma, ganglioglioma and ependymoma. Isoform 1 is highly expressed in brain and kidney, but not detected in liver. Isoform 3 is highly expressed in heart and pancreas, detected at lower levels in placenta, lung, pancreas and kidney, but is not detected in liver. Isoform 2 is expressed in cardiac and skeletal muscle. {ECO:0000269\|PubMed:11015561}.
Domain:		The C-terminal ANK repeats prevent the assembly of the supra- tetrameric filaments. {ECO:0000269\|PubMed:28526749}.
Domain:		A highly mobile activation loop at the dimer-dimer interface is important for enzyme activity. {ECO:0000250\|UniProtKB:D3Z7P3}.
Ptm:		Synthesized as a 74-kDa cytosolic precursor which is proteolytically processed by the mitochondrial-processing peptidase (MPP) via a 72-kDa intermediate to yield the mature mitochondrial 68- and 65-kDa subunits. {ECO:0000250\|UniProtKB:P13264}.
Disease:		Developmental and epileptic encephalopathy 71 (DEE71) [MIM:618328]: A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE71 is an autosomal recessive form with onset at birth. Death occurs in first weeks of life. {ECO:0000269\|PubMed:30575854}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development (CASGID) [MIM:618339]: An autosomal dominant disease characterized by infantile-onset cataract, erythematic subcutaneous nodules, profound developmental delay, self-injurious behavior, and intracerebral glutamate excess. Histopathologic analysis of skin lesions show deep perivascular and periglandular lymphohistiocytic infiltrates and pronounced leukocytoclasia at the surface of the dermis, focal vacuolar alterations, hyperkeratosis, and parakeratosis of the epidermis. {ECO:0000269\|PubMed:30239721}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Global developmental delay, progressive ataxia, and elevated glutamine (GDPAG) [MIM:618412]: An autosomal recessive disease characterized by early-onset delay in motor skills, delayed speech, progressive ataxia, and neurologic deterioration. Plasma glutamine is persistently elevated by a factor of 2.5 despite normal plasma ammonia levels. {ECO:0000269\|PubMed:30970188}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the glutaminase family. {ECO:0000305}.
Sequence caution:		Sequence=BAA74861.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};