GLS

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004359 glutaminase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically-inferred glutaminase activity. This is the well-established core molecular function of GLS, confirmed directly by multiple experimental structural-enzymology studies and by the UniProt catalytic-activity annotation (EC 3.5.1.2, L-glutamine + H2O = L-glutamate + NH4+). Supporting Evidence: file:human/GLS/GLS-uniprot.txt Reaction=L-glutamine + H2O = L-glutamate + NH4(+);
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference that GLS is active in the mitochondrion. Correct: the mature enzyme is a mitochondrial (matrix) protein. Accepted as a core location. Supporting Evidence: PMID:22228304 GAC is distinctly mitochondrial
GO:0006543 L-glutamine catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetically-inferred involvement in glutamine catabolism. This is the core biological process for GLS (glutaminolysis begins with glutamine hydrolysis). Accepted; also supported directly by IDA (PMID:22049910).
GO:0004359 glutaminase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assertion of glutaminase activity (multiple IEA methods, incl. RHEA/EC/InterPro). Correct and redundant with the experimental annotations of the same term. Accepted as core MF.
GO:0005739 mitochondrion	IEA GO_REF:0000044	ACCEPT	Summary: UniProt SubCell mapping to mitochondrion. Correct core location; redundant with experimental mitochondrial annotations.
GO:0005759 mitochondrial matrix	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assertion of mitochondrial matrix localization. Consistent with the mature 68-/65-kDa chains being matrix proteins per UniProt. This is the specific compartment within the mitochondrion; accepted. Supporting Evidence: file:human/GLS/GLS-uniprot.txt Mitochondrion matrix {ECO:0000250\|UniProtKB:P13264}.
GO:0005829 cytosol	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: UniProt SubCell mapping to cytosol. This reflects the ~74-kDa cytosolic precursor of isoform 1 before mitochondrial import, not a steady-state site of catalysis. Real but transient/non-core; keep as non-core. Supporting Evidence: file:human/GLS/GLS-uniprot.txt Cytoplasm, cytosol
GO:0006520 amino acid metabolic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA electronic annotation to the very general parent 'amino acid metabolic process'. Not wrong, but far less informative than the specific L-glutamine catabolic / L-glutamate biosynthetic terms that are directly supported. Keep as a non-core general grouping term.
GO:0006541 L-glutamine metabolic process	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro2GO electronic annotation to 'L-glutamine metabolic process', the parent of the specific catabolic term. Correct but general; the specific child GO:0006543 (L-glutamine catabolic process) is the appropriate core term and is already annotated. Generalize/keep as non-core.
GO:0006543 L-glutamine catabolic process	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl-Compara electronic transfer of glutamine catabolic process. Correct core BP; redundant with IBA and IDA annotations of the same term.
GO:0051289 protein homotetramerization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronic transfer of protein homotetramerization. GLS does form homotetramers (dimers of dimers), so this captures a real quaternary-structure property rather than the enzyme's pathway function. Keep as non-core.
GO:0097054 L-glutamate biosynthetic process	IEA GO_REF:0000107	ACCEPT	Summary: Electronic transfer of L-glutamate biosynthetic process. This is the product side of the glutaminase reaction and is a legitimate core BP; redundant with the IDA (PMID:22049910) and TAS (PMID:21757002) annotations of the same term.
GO:0062133 negative regulation of L-glutamine biosynthetic process	IDA PMID:16899818 Brain-specific BNIP-2-homology protein Caytaxin relocalises ...	MARK AS OVER ANNOTATED	Summary: Derived from the ATCAY/Caytaxin study (PMID:16899818). That paper shows that Caytaxin (ATCAY) binds and inhibits KGA and thereby lowers glutamate; it does not show that GLS itself negatively regulates glutamine biosynthesis. GLS degrades glutamine (catabolism) rather than regulating its synthesis, so this process term is a poor fit for GLS's own function. As an experimental IDA it is retained but flagged as an over-annotation. Reason: The study shows that Caytaxin (ATCAY) binds and inhibits KGA and so lowers glutamate; it does not show GLS acting on the regulation of glutamine synthesis. GLS hydrolyses glutamine (catabolism), so the process term fits GLS poorly. The row is an experimental IDA whose curator read the full paper, so it is flagged as over-annotation rather than removed. Supporting Evidence: PMID:16899818 It also reduced the steady-state levels of glutamate by inhibiting KGA enzyme activity.
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: HPA immunofluorescence localization to mitochondrion. Consistent with all other evidence; accepted as core location.
GO:0004359 glutaminase activity	EXP PMID:22538822 Structural basis for the allosteric inhibitory mechanism of ...	ACCEPT	Summary: Experimental glutaminase activity from the KGA structure/enzymology study (crystal structures with glutamate/glutamine substrate, catalytic-activity assays, active-site mutagenesis). Directly establishes the core molecular function. Accepted. Supporting Evidence: PMID:22538822 human kidney-type glutaminase isoform (KGA) is becoming an attractive target
GO:0004359 glutaminase activity	EXP PMID:24451979 Structural basis for the active site inhibition mechanism of...	ACCEPT	Summary: Experimental glutaminase activity confirmed by the cKGA active-site inhibition study: glutaminase assays plus active-site mutagenesis (Ser286, Lys289, Tyr249, Tyr466) that reduce activity. Directly supports the core MF. Accepted. Supporting Evidence: PMID:24451979 Glutaminase controls the first step in the glutaminolysis pathway by converting glutamine (Gln) to glutamate (Glu)
GO:0004359 glutaminase activity	EXP PMID:26988803 Design and evaluation of novel glutaminase inhibitors.	ACCEPT	Summary: Experimental glutaminase activity from the glutaminase-inhibitor design study, which assayed catalytic activity and solved KGA/GAC structures. Supports the core MF. Accepted.
GO:0004359 glutaminase activity	EXP PMID:28526749 The origin and evolution of human glutaminases and their aty...	ACCEPT	Summary: Experimental glutaminase activity from the glutaminase evolution/structure study (full-length KGA crystal structure with catalytic-activity determination). Supports the core MF. Accepted.
GO:0004359 glutaminase activity	EXP PMID:29317493 Characterization of the interactions of potent allosteric in...	ACCEPT	Summary: Experimental glutaminase activity from the GAC allosteric-inhibitor study, which measured enzymatic activity of recombinant GAC. Supports the core MF. Accepted. Supporting Evidence: PMID:29317493 glutaminase C (GAC), which catalyzes the first step in glutamine metabolism
GO:0005739 mitochondrion	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity transfer of mitochondrial localization from the rat ortholog (P13264). Correct core location; redundant with experimental evidence.
GO:0005739 mitochondrion	EXP PMID:22228304 Mitochondrial localization and structure-based phosphate act...	ACCEPT	Summary: Experimental demonstration that GAC is mitochondrial (subcellular-localization analysis). Directly supports the core mitochondrial localization. Accepted. Supporting Evidence: PMID:22228304 GAC is distinctly mitochondrial
GO:0005759 mitochondrial matrix	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity transfer of mitochondrial matrix localization from the rat ortholog. Consistent with the mature matrix-resident chains; accepted as the specific compartment. Supporting Evidence: file:human/GLS/GLS-uniprot.txt Mitochondrion matrix {ECO:0000250\|UniProtKB:P13264}.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-70609	ACCEPT	Summary: Reactome traceable assertion placing the glutaminase reaction in the mitochondrial matrix. Consistent with UniProt; accepted as the specific compartment of catalysis.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput mitochondrial proteomics detection of GLS. Consistent with the established mitochondrial localization; accepted (corroborating, non-core relative to the direct localization studies).
GO:0090461 intracellular glutamate homeostasis	IMP PMID:30239721 GLS hyperactivity causes glutamate excess, infantile catarac...	ACCEPT	Summary: Supported by the gain-of-function Ser482Cys study: hyperactive GLS raises glutamate and lowers glutamine in patient cells, and inhibiting GLS reverses the phenotype, directly implicating GLS in setting intracellular glutamate levels. Accepted as a physiological process downstream of the core catalytic function. Supporting Evidence: PMID:30239721 increased glutamate and decreased glutamine concentrations were measured in urine and fibroblasts
GO:0005515 protein binding	IPI PMID:16899818 Brain-specific BNIP-2-homology protein Caytaxin relocalises ...	REMOVE	Summary: IPI capturing the direct interaction with ATCAY/Caytaxin (Q86WG3), a brain-specific regulator that relocalizes GLS and inhibits its activity. The interaction is real and biologically meaningful, but bare 'protein binding' is uninformative as a molecular function; the regulatory biology is captured in the notes. Reason: Bare protein binding is uninformative. In this study Caytaxin (ATCAY) binds kidney-type glutaminase and relocalises it to neurite terminals; GLS is the cargo and regulated partner, and the paper supports no more specific molecular function for GLS. Removal does not mean the interaction is false. Supporting Evidence: PMID:16899818 binding studies showed that they interact with each other directly
GO:0005739 mitochondrion	IDA PMID:16899818 Brain-specific BNIP-2-homology protein Caytaxin relocalises ...	ACCEPT	Summary: Direct localization of KGA to mitochondria (baseline, before ATCAY-induced relocalization to neurite terminals). Supports the core mitochondrial location. Accepted. Supporting Evidence: PMID:16899818 relocalised KGA from the mitochondria to neurite terminals
GO:0004359 glutaminase activity	IDA PMID:22049910 Full-length human glutaminase in complex with an allosteric ...	ACCEPT	Summary: Direct assay of glutaminase activity on full-length human GLS/GAC (kinetics; KM for glutamine reported in UniProt). Definitive support for the core molecular function. Accepted. Supporting Evidence: PMID:22049910 Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia.
GO:0006543 L-glutamine catabolic process	IDA PMID:22049910 Full-length human glutaminase in complex with an allosteric ...	ACCEPT	Summary: Direct evidence that GLS catalyzes the committed catabolic step for glutamine (glutamine -> glutamate + ammonia). Core biological process. Accepted. Supporting Evidence: PMID:22049910 Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia.
GO:0051289 protein homotetramerization	IDA PMID:22049910 Full-length human glutaminase in complex with an allosteric ...	KEEP AS NON CORE	Summary: Direct structural evidence for the GAC homotetramer (full-length crystal structure; BPTES binds at the tetramer interface). This is a genuine quaternary-structure property that underlies phosphate activation, but it is not the enzyme's core pathway function. Keep as non-core. Supporting Evidence: PMID:22049910 Two BPTES molecules bind at an interface region of the GAC tetramer
GO:0097054 L-glutamate biosynthetic process	IDA PMID:22049910 Full-length human glutaminase in complex with an allosteric ...	ACCEPT	Summary: Direct evidence that GLS produces L-glutamate from glutamine. This is the product side of the glutaminase reaction and is a legitimate core BP (glutamate biosynthesis via glutamine hydrolysis). Accepted. Supporting Evidence: PMID:22049910 Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia.
GO:0097054 L-glutamate biosynthetic process	TAS PMID:21757002 The nuclear receptor FXR regulates hepatic transport and met...	ACCEPT	Summary: Traceable assertion (FXR/hepatic glutamine-glutamate metabolism review context) that glutaminase generates glutamate. Consistent with the core function; the cited paper is about FXR regulation of hepatic glutamine/glutamate metabolism and only contextually establishes GLS's role. Accepted as corroborating (non-core relative to the direct enzymology).
GO:0004359 glutaminase activity	NAS PMID:10719215 Isolation, characterization and expression of a human brain ...	ACCEPT	Summary: Non-traceable/author-stated glutaminase activity from the human brain glutaminase cDNA cloning paper (recombinant enzyme was active). Correct core MF; redundant with the experimental annotations. Supporting Evidence: PMID:10719215 express high levels of properly processed and active glutaminase
GO:0005739 mitochondrion	NAS PMID:10719215 Isolation, characterization and expression of a human brain ...	ACCEPT	Summary: Author-stated mitochondrial localization inferred from the N-terminal mitochondrial targeting signal in the human brain glutaminase cDNA. Correct core location; redundant with direct evidence. Supporting Evidence: PMID:10719215 N-terminal mitochondrial targeting signal
GO:0006543 L-glutamine catabolic process	NAS PMID:10719215 Isolation, characterization and expression of a human brain ...	ACCEPT	Summary: Author-stated involvement in glutamine metabolism (the cloned enzyme catalyzes a key reaction in glutamine metabolism and neurotransmitter synthesis). Core BP; redundant with the IBA/IDA annotations. Supporting Evidence: PMID:10719215 a key reaction in the metabolism of glutamine and the synthesis of important excitatory and inhibitory neurotransmitters
GO:0004359 glutaminase activity	NAS PMID:11015561 Cloning and analysis of unique human glutaminase isoforms ge...	ACCEPT	Summary: Author-stated glutaminase activity from the isoform-cloning paper (hKGA/hGAC are active kidney-type glutaminases; hGAC has high glutaminase activity in breast cancer cells). Correct core MF; redundant with experimental annotations. Supporting Evidence: PMID:11015561 a high rate of glutamine utilization and glutaminase activity

Gene Description

Existing Annotations Review

Core Functions

Hydrolyzes L-glutamine to L-glutamate and ammonia in the mitochondrial matrix (glutaminase activity, EC 3.5.1.2), the first, committed step of glutaminolysis that supplies glutamate for TCA-cycle anaplerosis, renal ammoniagenesis, and the neuronal glutamate/glutamine cycle.

References

📚 Additional Documentation

Notes

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