GLUD2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004352 L-glutamate dehydrogenase (NAD+) activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) propagation of NAD+-dependent glutamate dehydrogenase activity across the GDH family. GLUD2 is a bona fide glutamate dehydrogenase and this catalytic activity is directly supported by experiment. The NAD+ cofactor is one of the two cofactors GLUD2 uses; the dual-cofactor term GO:0004353 is the most complete single description of the EC 1.4.1.3 activity. Supporting Evidence: file:human/GLUD2/GLUD2-uniprot.txt Reaction=L-glutamate + NAD(+) + H2O = 2-oxoglutarate + NH4(+) + NADH +
GO:0006538 L-glutamate catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic propagation of the glutamate catabolic (oxidative deamination) process. Consistent with the core catabolic direction of GDH catalysis, which is experimentally documented for GLUD2. Accept as a core biological process. Supporting Evidence: file:human/GLUD2/GLUD2-uniprot.txt Reaction=L-glutamate + NAD(+) + H2O = 2-oxoglutarate + NH4(+) + NADH +
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic propagation of mitochondrial localization. GLUD2 is experimentally shown to be specifically targeted to mitochondria and localizes to the mitochondrial matrix. This general mitochondrion assignment is correct; the more specific mitochondrial matrix location (GO:0005759) is captured by the dedicated matrix annotations. Accept. Supporting Evidence: file:human/GLUD2/GLUD2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix
GO:0004352 L-glutamate dehydrogenase (NAD+) activity	IEA GO_REF:0000120	ACCEPT	Summary: Automated (ARBA/RHEA) assignment of NAD+-dependent glutamate dehydrogenase activity. This matches the experimentally documented catalytic activity and one of the two Rhea reactions annotated in UniProt. Accept as a cofactor-specific view of the core function. Supporting Evidence: file:human/GLUD2/GLUD2-uniprot.txt Reaction=L-glutamate + NAD(+) + H2O = 2-oxoglutarate + NH4(+) + NADH +
GO:0004353 L-glutamate dehydrogenase [NAD(P)+] activity	IEA GO_REF:0000003	ACCEPT	Summary: EC 1.4.1.3 -> GO mapping to the dual-cofactor glutamate dehydrogenase activity. UniProt records both NAD+ and NADP+ catalytic reactions (EC 1.4.1.3), so this dual-cofactor term is the most complete single description of the GLUD2 molecular function. This is the chosen core molecular function. Supporting Evidence: file:human/GLUD2/GLUD2-uniprot.txt Reaction=L-glutamate + NADP(+) + H2O = 2-oxoglutarate + NH4(+) + NADPH
GO:0004354 L-glutamate dehydrogenase (NADP+) activity	IEA GO_REF:0000116	ACCEPT	Summary: Rhea-based automated assignment of NADP+-dependent glutamate dehydrogenase activity. UniProt records the NADP+ reaction for GLUD2 (EC 1.4.1.3), so this cofactor-specific term is correct. Accept as a valid cofactor-specific view of the core function. Supporting Evidence: file:human/GLUD2/GLUD2-uniprot.txt Reaction=L-glutamate + NADP(+) + H2O = 2-oxoglutarate + NH4(+) + NADPH
GO:0005525 GTP binding	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Automated (ARBA) assignment of GTP binding. GDH enzymes possess a GTP allosteric site. For GLUD2 specifically, this site is present but the enzyme is essentially insensitive to GTP inhibition in its basal state (a hallmark adaptive difference from GLUD1); there is a concordant experimental IDA for GTP binding (PMID:11032875). GTP binding is a regulatory, non-core feature, so keep as non-core. Supporting Evidence: PMID:11032875 whereas nonactivated GLUD2 GDH was totally insensitive to this compound (IC(50) > 5,000 microM:)
GO:0005759 mitochondrial matrix	IEA GO_REF:0000044	ACCEPT	Summary: UniProt subcellular-location keyword mapping to mitochondrial matrix. This is the experimentally supported location (UniProt SUBCELLULAR LOCATION, evidence PubMed:22709669) and is the correct, specific cellular component for GLUD2. Accept as the core location. Supporting Evidence: file:human/GLUD2/GLUD2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix
GO:0006520 amino acid metabolic process	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro2GO assignment of the general amino-acid metabolic process. Correct but high-level: GLUD2 acts specifically on L-glutamate. The more specific glutamate catabolic/metabolic terms (GO:0006538, GO:0006536) are better representatives of the core process; keep this broad parent as non-core. Supporting Evidence: file:human/GLUD2/GLUD2-uniprot.txt Reaction=L-glutamate + NAD(+) + H2O = 2-oxoglutarate + NH4(+) + NADH +
GO:0006538 L-glutamate catabolic process	IEA GO_REF:0000117	ACCEPT	Summary: Automated (ARBA) assignment of the glutamate catabolic process, redundant with the experimental IDA (PMID:11032875) and IBA for the same term. Correct and represents the core catabolic direction of GDH. Accept. Supporting Evidence: file:human/GLUD2/GLUD2-uniprot.txt Reaction=L-glutamate + NAD(+) + H2O = 2-oxoglutarate + NH4(+) + NADH +
GO:0016491 oxidoreductase activity	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro2GO assignment of the very general oxidoreductase-activity parent. Correct (GDH is an oxidoreductase) but far too broad; the specific glutamate dehydrogenase activity terms capture the function. Keep as non-core. Supporting Evidence: file:human/GLUD2/GLUD2-uniprot.txt Reaction=L-glutamate + NAD(+) + H2O = 2-oxoglutarate + NH4(+) + NADH +
GO:0016639 oxidoreductase activity, acting on the CH-NH2 group of donors, NAD or NADP as acceptor	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro2GO assignment of the intermediate oxidoreductase parent (acting on CH-NH2 donors with NAD/NADP acceptor). Correct and closer than the bare oxidoreductase term, but still a parent of the specific glutamate dehydrogenase activity. Keep as non-core; the specific GO:0004353 is the core molecular function. Supporting Evidence: file:human/GLUD2/GLUD2-uniprot.txt Reaction=L-glutamate + NAD(+) + H2O = 2-oxoglutarate + NH4(+) + NADH +
GO:0043531 ADP binding	IEA GO_REF:0000117	ACCEPT	Summary: Automated (ARBA) assignment of ADP binding, concordant with the experimental IDA (PMID:12742085). ADP is the physiologically salient allosteric activator of GLUD2, which requires high ADP for full activation. This regulatory binding is well supported; accept. Supporting Evidence: PMID:11032875 the presence of ADP (10-50 microM:) sensitized the two isoenzymes to L-leucine
GO:0070728 L-leucine binding	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Automated (ARBA) assignment of L-leucine binding, concordant with the experimental IDA (PMID:12742085). L-leucine is an allosteric activator of GDH; GLUD2 is very strongly activated by L-leucine. Regulatory-effector binding, kept as non-core. Supporting Evidence: PMID:11032875 L-leucine, at 1.0 mM:, enhanced the activity of the nerve tissue-specific (GLUD2-derived) enzyme by approximately 1,600%
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: High-throughput AP-MS interactome screen (BioPlex) reporting a protein-protein interaction; the WITH field is UniProtKB:P00367 (GLUD1). Consistent with the documented GLUD1-GLUD2 association within the hexameric GDH family, but the bare "protein binding" term is uninformative about molecular function. Not removed (experimental IPI); marked as over-annotated. Supporting Evidence: file:human/GLUD2/GLUD2-uniprot.txt P49448; P00367: GLUD1; NbExp=2
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Second high-throughput AP-MS interactome screen (BioPlex 3) again reporting an interaction with UniProtKB:P00367 (GLUD1). As above, the bare "protein binding" term is uninformative. Retained as experimental evidence but marked as over-annotated. Supporting Evidence: file:human/GLUD2/GLUD2-uniprot.txt P49448; P00367: GLUD1; NbExp=2
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: Human Protein Atlas immunofluorescence localizing GLUD2 to the mitochondrion. Consistent with the established mitochondrial-matrix localization. The specific matrix term (GO:0005759) is captured elsewhere; accept this mitochondrion annotation as supporting localization evidence. Supporting Evidence: file:human/GLUD2/GLUD2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput mitochondrial-proteome study identifying GLUD2 as a mitochondrial protein. Corroborates the mitochondrial localization documented by lower-throughput methods. Accept. Supporting Evidence: file:human/GLUD2/GLUD2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix
GO:0005829 cytosol	IDA NOT PMID:18688271 Mitochondrial targeting adaptation of the hominoid-specific ...	ACCEPT	Summary: Correct NOT annotation. Unlike its paralog GLUD1 (which is both mitochondrial and cytoplasmic), GLUD2 is specifically targeted to mitochondria because of a positively selected E7K substitution in its mitochondrial targeting sequence, and is not appreciably cytosolic. Accept this well-supported negative annotation. Supporting Evidence: PMID:18688271 whereas GLUD1 localizes to the mitochondria as well as the cytoplasm, GLUD2 is specifically targeted to mitochondria
GO:0070728 L-leucine binding	IDA PMID:12742085 Study of structure-function relationships in human glutamate...	KEEP AS NON CORE	Summary: Experimental evidence that L-leucine binds and allosterically activates the GLUD2 isoenzyme (the enzyme is amenable to full activation by ADP and/or L-leucine). This is a regulatory-effector binding, not the catalytic core; keep as non-core. Supporting Evidence: PMID:12742085 it remains amenable to full activation by ADP and/or L-leucine
GO:0005525 GTP binding	IDA PMID:11032875 Nerve tissue-specific (GLUD2) and housekeeping (GLUD1) human...	KEEP AS NON CORE	Summary: Experimental characterization of GTP interaction with GLUD2. Basal GLUD2 is essentially insensitive to GTP inhibition (IC50 > 5000 uM), though ADP/leucine-activated GLUD2 can be inhibited by GTP at much higher concentrations than GLUD1. GTP binding at the allosteric site is a regulatory, non-core feature; keep as non-core. Supporting Evidence: PMID:11032875 GLUD2 GDH activated by ADP and/or L-leucine was amenable to this inhibition
GO:0005739 mitochondrion	IDA PMID:18688271 Mitochondrial targeting adaptation of the hominoid-specific ...	ACCEPT	Summary: Direct experimental (fluorescent-fusion) evidence that GLUD2 localizes specifically to mitochondria. Consistent with the mitochondrial-matrix core location. Accept. Supporting Evidence: PMID:18688271 GLUD2 from all apes localizes predominantly to mitochondria
GO:0043531 ADP binding	IDA PMID:12742085 Study of structure-function relationships in human glutamate...	ACCEPT	Summary: Experimental evidence that ADP binds and allosterically activates GLUD2; the GLUD2 enzyme has low basal activity and is rendered dependent on ADP for its function. ADP is the physiologically salient allosteric activator, adapting GLUD2 to a high ADP:ATP ratio. Accept as a functionally important (regulatory) binding activity. Supporting Evidence: PMID:12742085 it remains amenable to full activation by ADP and/or L-leucine
GO:0097054 L-glutamate biosynthetic process	IDA PMID:11032875 Nerve tissue-specific (GLUD2) and housekeeping (GLUD1) human...	KEEP AS NON CORE	Summary: The GDH reaction is reversible, so the enzyme can run in the reductive-amination (glutamate-synthesizing) direction as well as the catabolic direction. Kinetic characterization of GLUD2 examined both alpha-ketoglutarate and glutamate as substrates, supporting a role in glutamate biosynthesis. This synthetic direction is a secondary (non-core) physiological role relative to the catabolic recycling of glutamate; keep as non-core. Supporting Evidence: PMID:11032875 Kinetic studies revealed significant differences in the K:(m) values obtained for alpha-ketoglutarate and glutamate
GO:0004353 L-glutamate dehydrogenase [NAD(P)+] activity	IDA PMID:11032875 Nerve tissue-specific (GLUD2) and housekeeping (GLUD1) human...	ACCEPT	Summary: Direct assay of the recombinant GLUD2 isoenzyme as a glutamate dehydrogenase using both NAD(P) cofactors (EC 1.4.1.3). This dual-cofactor term is the core molecular function of GLUD2. Accept. Supporting Evidence: PMID:11032875 Human glutamate dehydrogenase (GDH), an enzyme central to the metabolism of glutamate
GO:0006538 L-glutamate catabolic process	IDA PMID:11032875 Nerve tissue-specific (GLUD2) and housekeeping (GLUD1) human...	ACCEPT	Summary: Experimental support for GLUD2 participation in glutamate catabolism (oxidative deamination of glutamate). This is the core catabolic biological process; accept. Supporting Evidence: PMID:11032875 Human glutamate dehydrogenase (GDH), an enzyme central to the metabolism of glutamate
GO:0004352 L-glutamate dehydrogenase (NAD+) activity	IDA PMID:15578726 Molecular basis of human glutamate dehydrogenase regulation ...	ACCEPT	Summary: Direct experimental characterization of the recombinant GLUD2 isoenzyme's catalytic activity (baseline activity, allosteric regulation). Supports NAD-dependent glutamate dehydrogenase activity, a cofactor-specific view of the core function. Accept. Supporting Evidence: PMID:15578726 The two isoenzymes differ markedly in their baseline activities, allosteric regulation, and thermal stability
GO:0004352 L-glutamate dehydrogenase (NAD+) activity	IDA PMID:8207021 Novel human glutamate dehydrogenase expressed in neural and ...	ACCEPT	Summary: The founding GLUD2 paper: recombinant expression of the GLUD2 cDNA yielded a protein capable of catalyzing the oxidative deamination of glutamate, with catalytic properties similar to native human brain GDH. Direct support for glutamate dehydrogenase activity. Accept as a cofactor-specific view of the core molecular function. Supporting Evidence: PMID:8207021 producing a protein capable of catalyzing the oxidative deamination of glutamate
GO:0006536 glutamate metabolic process	IDA PMID:8207021 Novel human glutamate dehydrogenase expressed in neural and ...	ACCEPT	Summary: GLUD2 is an enzyme central to glutamate metabolism, catalyzing the interconversion of glutamate and 2-oxoglutarate. This is a core biological process for the gene. Accept. Supporting Evidence: PMID:8207021 Glutamate dehydrogenase, an enzyme central to glutamate metabolism

Gene Description

Existing Annotations Review

Core Functions

Reversible oxidative deamination of L-glutamate to 2-oxoglutarate and ammonia, using NAD+ or NADP+ as cofactor (EC 1.4.1.3), in the mitochondrial matrix. This connects amino-acid / nitrogen metabolism to the TCA cycle and, in astrocytes, supports catabolic recycling of neurotransmitter glutamate.

Allosteric activation of GDH catalytic activity by ADP. GLUD2 has low basal activity and is dependent on ADP (and L-leucine) for full activation, an adaptation to the high ADP:ATP ratio of synaptic astrocytes during glutamatergic transmission.

References

📚 Additional Documentation

Notes

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