GLS2

UniProt ID: Q9UI32
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

GLS2 encodes the liver-type (L-type) phosphate-activated glutaminase (glutaminase 2; also called LGA/GAB), a mitochondrial amidohydrolase (EC 3.5.1.2) that catalyzes the hydrolysis of L-glutamine to L-glutamate and ammonia. It is one of the two human glutaminase genes (the other being the kidney-type GLS) and assembles as a homotetramer (dimer of dimers) with a catalytic glutaminase domain and a C-terminal pair of ankyrin repeats. The glutamate produced feeds alpha-ketoglutarate into the TCA cycle, supporting mitochondrial respiration and ATP generation, and serves as a precursor for glutathione synthesis, so GLS2 contributes to cellular antioxidant defense by lowering reactive oxygen species. In liver it also supplies ammonia to the urea cycle. GLS2 is highly expressed in liver and additionally in brain and pancreas, with a distinct kinetic and regulatory profile from GLS. Its expression is directly induced by the tumor suppressor p53, and GLS2 is frequently down-regulated in hepatocellular carcinoma and some other tumors, consistent with a tumor-suppressive role.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0004359 glutaminase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Core molecular function. GLS2 is a glutaminase (EC 3.5.1.2) that hydrolyzes L-glutamine to L-glutamate plus ammonia; the GO:0004359 definition matches the UniProt catalytic-activity reaction exactly. Well supported by biochemistry, structure, and phylogeny (whole family are glutaminases).
Supporting Evidence:
file:human/GLS2/GLS2-uniprot.txt
Reaction=L-glutamine + H2O = L-glutamate + NH4(+)
GO:0005739 mitochondrion
IBA
GO_REF:0000033 		ACCEPT
Summary: Correct core localization. GLS2 has an N-terminal mitochondrial transit peptide and is a mitochondrial matrix enzyme, confirmed experimentally (IDA) and by the whole glutaminase family.
Supporting Evidence:
file:human/GLS2/GLS2-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion
GO:0006543 L-glutamine catabolic process
IBA
GO_REF:0000033 		ACCEPT
Summary: Core biological process. Glutaminase-mediated glutamine hydrolysis is the committed step of glutamine catabolism; UniProt FUNCTION explicitly assigns GLS2 a role in the regulation of glutamine catabolism.
Supporting Evidence:
file:human/GLS2/GLS2-uniprot.txt
Plays an important role in the regulation of glutamine
GO:0004359 glutaminase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic (InterPro/RHEA/EC) assignment of the same core glutaminase activity; consistent with the experimental and phylogenetic evidence. Redundant with the IBA and TAS annotations but correct.
Supporting Evidence:
file:human/GLS2/GLS2-uniprot.txt
Reaction=L-glutamine + H2O = L-glutamate + NH4(+)
GO:0005739 mitochondrion
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic subcellular-location mapping to mitochondrion; agrees with the curated UniProt subcellular location and experimental IDA evidence.
Supporting Evidence:
file:human/GLS2/GLS2-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion
GO:0005759 mitochondrial matrix
IEA
GO_REF:0000117 		ACCEPT
Summary: ARBA electronic annotation to the mitochondrial matrix, the specific compartment for a matrix-soluble glutaminase. More precise than the parent mitochondrion term and consistent with Reactome TAS annotations.
GO:0006520 amino acid metabolic process
IEA
GO_REF:0000117 		KEEP AS NON CORE
Summary: Not wrong (glutamine/glutamate are amino acids) but very general; the specific processes L-glutamine catabolic process and L-glutamate biosynthetic process are the informative terms and are captured elsewhere. Kept as non-core high-level grouping.
GO:0006541 L-glutamine metabolic process
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: InterPro2GO electronic annotation. Correct but less specific than L-glutamine catabolic process (GO:0006543), which better describes the directional hydrolysis GLS2 performs. Kept as a non-core parent term.
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		MARK AS OVER ANNOTATED
Summary: High-throughput binary interactome (HuRI) IPI capturing interactions with HIP1 (O00291) and XAF1 (Q6GPH4). "Protein binding" is uninformative as a molecular function and these are large-scale screen hits rather than characterized functional partners; retained per policy but flagged as over-annotation.
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		MARK AS OVER ANNOTATED
Summary: High-throughput affinity-purification interactome (BioPlex) IPI (with HIP1, O00291). Same rationale as the HuRI annotation: uninformative bare protein-binding term from a proteome-scale screen. Retained per policy, flagged as over-annotation.
GO:0004359 glutaminase activity
ISS
GO_REF:0000024 		ACCEPT
Summary: Sequence-similarity transfer of glutaminase activity from mouse Gls2 (Q571F8), the basis of the curated EC/catalytic-activity assignment. Correct core function; redundant with the IBA/IEA/TAS glutaminase annotations.
Supporting Evidence:
file:human/GLS2/GLS2-uniprot.txt
EC=3.5.1.2 {ECO:0000250|UniProtKB:Q571F8}
GO:0005739 mitochondrion
HTP
PMID:34800366
Quantitative high-confidence human mitochondrial proteome an... 		ACCEPT
Summary: High-throughput mitochondrial proteomics dataset localizing GLS2 to the mitochondrion. Consistent with the curated location and the low-throughput IDA; correct.
GO:0005759 mitochondrial matrix
TAS
Reactome:R-HSA-5632924 		ACCEPT
Summary: Reactome TAS placing GLS2 in the mitochondrial matrix within the "TP53 stimulates GLS2 transcription" pathway. Correct compartment for this soluble matrix enzyme.
GO:0005759 mitochondrial matrix
TAS
Reactome:R-HSA-70609 		ACCEPT
Summary: Reactome TAS placing the glutaminase reaction (glutamine + H2O => glutamate + NH4+) in the mitochondrial matrix. Correct core localization; redundant with the other matrix annotation but well supported.
GO:0005739 mitochondrion
IDA
PMID:20351271
Phosphate-activated glutaminase (GLS2), a p53-inducible regu... 		ACCEPT
Summary: Experimental (IDA) mitochondrial localization from the Suzuki et al. GLS2 study, which characterizes the enzyme as phosphate-activated mitochondrial glutaminase. This is the primary experimental support for the core mitochondrial location.
Supporting Evidence:
PMID:20351271
phosphate-activated mitochondrial glutaminase
GO:0042981 regulation of apoptotic process
IMP
PMID:20351271
Phosphate-activated glutaminase (GLS2), a p53-inducible regu... 		KEEP AS NON CORE
Summary: Experimental IMP: GLS2 knockdown raises ROS and coincides with stimulation of p53-induced cell death, placing GLS2 upstream of the apoptotic response. This is a genuine downstream/regulatory consequence of GLS2's metabolic-antioxidant activity rather than its direct molecular function, so retained as non-core.
Supporting Evidence:
PMID:20351271
coincide with stimulation of p53-induced cell death
GO:0072593 reactive oxygen species metabolic process
IMP
PMID:20351271
Phosphate-activated glutaminase (GLS2), a p53-inducible regu... 		KEEP AS NON CORE
Summary: Experimental IMP: elevated GLS2 lowers intracellular ROS (via glutamate/glutathione), and GLS2 knockdown increases ROS. A real, physiologically important role, but a downstream effect of the enzymatic activity and the p53 antioxidant program rather than the core molecular function; kept as non-core.
Supporting Evidence:
PMID:20351271
lowers intracellular reactive oxygen species (ROS) levels
GO:0005515 protein binding
IPI
PMID:11163757
The C-terminus of human glutaminase L mediates association w... 		MARK AS OVER ANNOTATED
Summary: Yeast two-hybrid interaction of the GLS2 C-terminus with PDZ-domain proteins (alpha1-syntrophin SNTA1 and GIP/TAX1BP3; WITH=O14907). Biologically meaningful (the C-terminal -ESXV motif mediates PDZ binding), but "protein binding" itself is uninformative as a molecular-function term. Retained per policy, marked over-annotated; the specific PDZ interaction is noted in the gene notes.
Supporting Evidence:
PMID:11163757
the sequence -ESXV as essential for
GO:0004359 glutaminase activity
TAS
PMID:10620514
Molecular cloning, sequencing and expression studies of the ... 		ACCEPT
Summary: Author-statement (TAS) glutaminase activity from the original cloning of the human liver-type (breast-cancer ZR-75) glutaminase, which established GLS2 as a phosphate-activated glutaminase. Supports the core molecular function.
Supporting Evidence:
PMID:10620514
Phosphate-activated glutaminase (GA)
GO:0005739 mitochondrion
TAS
PMID:10620514
Molecular cloning, sequencing and expression studies of the ... 		ACCEPT
Summary: TAS mitochondrial localization inferred from the N-terminal mitochondrial import presequence identified in the original cloning paper. Consistent with the experimental IDA and curated location.
Supporting Evidence:
PMID:10620514
a putative mitochondrial import presequence of 14 residues
GO:0006520 amino acid metabolic process
TAS
PMID:10620514
Molecular cloning, sequencing and expression studies of the ... 		KEEP AS NON CORE
Summary: High-level author-statement grouping term. Correct (glutamine/glutamate metabolism) but general; the specific glutamine catabolism / glutamate biosynthesis processes are the informative terms. Kept as non-core.
GO:0097054 L-glutamate biosynthetic process
IEA
GO_REF:0000033 		NEW
Summary: Proposed as a core process not currently in GOA. GLS2 produces L-glutamate as its reaction product; the UniProt DR line carries the now-obsolete GO:0006537 "glutamate biosynthetic process" (IBA), whose current equivalent is GO:0097054 "L-glutamate biosynthetic process". Added here as the up-to-date term for the glutamate-generating role. Not present in the GOA TSV, so marked NEW.
Supporting Evidence:
file:human/GLS2/GLS2-uniprot.txt
Reaction=L-glutamine + H2O = L-glutamate + NH4(+)

Core Functions

Mitochondrial phosphate-activated glutaminase that hydrolyzes L-glutamine to L-glutamate and ammonia (EC 3.5.1.2), the defining enzymatic function of GLS2.

Molecular Function:
glutaminase activity
Directly Involved In:
L-glutamine catabolic process L-glutamate biosynthetic process
Cellular Locations:
mitochondrial matrix mitochondrion
Substrates:
L-glutamine
Supporting Evidence:
  • file:human/GLS2/GLS2-uniprot.txt
    Reaction=L-glutamine + H2O = L-glutamate + NH4(+)
  • PMID:20378837
    GLS2 encodes a mitochondrial glutaminase catalyzing the hydrolysis of glutamine to glutamate
  • file:human/GLS2/GLS2-uniprot.txt
    Plays an important role in the regulation of glutamine

References

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📚 Additional Documentation

Notes

(GLS2-notes.md)

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