GLUD1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004352 L-glutamate dehydrogenase (NAD+) activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (PAN-GO) inference of the NAD(+)-dependent glutamate dehydrogenase activity. This is the well-established catalytic activity of GLUD1 and is directly supported by human experimental data. Because GLUD1 is a genuine dual-cofactor enzyme using both NAD(+) and NADP(+), the umbrella term GO:0004353 [NAD(P)+] is the most representative core function; the NAD(+)-specific term is accurate as a component of that activity. Supporting Evidence: file:human/GLUD1/GLUD1-uniprot.txt Mitochondrial glutamate dehydrogenase that catalyzes the
GO:0006538 L-glutamate catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference that GLUD1 participates in glutamate catabolism. This is the core biological process the enzyme executes (oxidative deamination of glutamate) and is experimentally supported in human. Supporting Evidence: PMID:6121377 Decreased glutamate
GO:0005739 mitochondrion	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic inference of mitochondrial localization. Correct; the enzyme is predominantly mitochondrial. The more specific and experimentally supported location is the mitochondrial matrix (GO:0005759), so this general term is retained as accurate but non-core. Supporting Evidence: file:human/GLUD1/GLUD1-uniprot.txt translocates into the mitochondria, only a small amount of the protein
GO:0004352 L-glutamate dehydrogenase (NAD+) activity	IEA GO_REF:0000120	ACCEPT	Summary: Automated (ARBA/RHEA) assignment of NAD(+)-dependent glutamate dehydrogenase activity, consistent with EC 1.4.1.3 and the RHEA:15133 reaction listed in UniProt. Accurate and experimentally corroborated. Supporting Evidence: file:human/GLUD1/GLUD1-uniprot.txt Reaction=L-glutamate + NAD(+) + H2O = 2-oxoglutarate
GO:0004353 L-glutamate dehydrogenase [NAD(P)+] activity	IEA GO_REF:0000003	ACCEPT	Summary: EC-mapping (EC 1.4.1.3) assignment of the dual-cofactor [NAD(P)+] glutamate dehydrogenase activity. This is the single most representative molecular function of GLUD1, which uses both NAD(+) and NADP(+); it is experimentally supported and designated core. Supporting Evidence: PMID:11254391 only animal GDH utilizes
GO:0004354 L-glutamate dehydrogenase (NADP+) activity	IEA GO_REF:0000116	ACCEPT	Summary: Automated (RHEA:11612) assignment of NADP(+)-dependent glutamate dehydrogenase activity. GLUD1 genuinely uses NADP(+) as well as NAD(+); the NADP(+) reaction is experimentally documented (PMID:11032875) and listed in UniProt. Supporting Evidence: file:human/GLUD1/GLUD1-uniprot.txt Reaction=L-glutamate + NADP(+) + H2O = 2-oxoglutarate
GO:0005525 GTP binding	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA electronic assignment of GTP binding. GTP is the major allosteric inhibitor of GLUD1 and binds a defined regulatory site; this is supported by an experimental IDA annotation (PMID:11032875) and by GTP-binding residues in UniProt. Kept as an accurate regulatory-ligand binding function (non-core). Supporting Evidence: file:human/GLUD1/GLUD1-uniprot.txt Inhibited by GTP and ATP
GO:0005739 mitochondrion	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: UniProt subcellular-location keyword mapping to mitochondrion. Correct and redundant with the experimental IDA mitochondrion annotations; retained as accurate but non-core relative to mitochondrial matrix. Supporting Evidence: file:human/GLUD1/GLUD1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: UniProt subcellular-location keyword mapping to endoplasmic reticulum. This reflects a genuine but minor extramitochondrial pool of GLUD1; it is not the core site of function. Supporting Evidence: PMID:19448744 part of the protein localizes to the endoplasmic reticulum
GO:0006520 amino acid metabolic process	IEA GO_REF:0000002	MODIFY	Summary: InterPro2GO assignment of a very general amino-acid metabolic process. GLUD1 indeed acts in amino-acid (glutamate) metabolism, but the specific, better term is L-glutamate catabolic process (GO:0006538), which is already annotated experimentally. This general term should be replaced by the specific one. Proposed replacements: L-glutamate catabolic process Supporting Evidence: file:human/GLUD1/GLUD1-uniprot.txt catalyzes the
GO:0006538 L-glutamate catabolic process	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic assignment of glutamate catabolism, redundant with the experimental IDA/IBA annotations to the same term. Accurate core process. Supporting Evidence: PMID:11903050 catalyses the reversible oxidative deamination of l-glutamate to 2-oxoglutarate in the mitochondrial matrix
GO:0016491 oxidoreductase activity	IEA GO_REF:0000002	MODIFY	Summary: InterPro2GO high-level oxidoreductase activity. Correct but far too general; the specific catalytic function is L-glutamate dehydrogenase [NAD(P)+] activity (GO:0004353), which is annotated experimentally. Replace with the specific term. Proposed replacements: L-glutamate dehydrogenase [NAD(P)+] activity Supporting Evidence: PMID:11254391 oxidative
GO:0016639 oxidoreductase activity, acting on the CH-NH2 group of donors, NAD or NADP as acceptor	IEA GO_REF:0000002	MODIFY	Summary: InterPro2GO assignment of the parent class of amino-acid dehydrogenase activity. Accurate but a generalization of the specific glutamate dehydrogenase [NAD(P)+] activity (GO:0004353). Replace with the specific term. Proposed replacements: L-glutamate dehydrogenase [NAD(P)+] activity Supporting Evidence: PMID:11254391 deamination of l-glutamate to 2-oxoglutarate
GO:0043531 ADP binding	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic assignment of ADP binding, redundant with the experimental IDA ADP-binding annotation (PMID:12742085). ADP is the principal allosteric activator of GLUD1 and binds a defined site; this is a core regulatory-ligand binding function. Supporting Evidence: file:human/GLUD1/GLUD1-uniprot.txt Activated by ADP
GO:0070728 L-leucine binding	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA electronic assignment of L-leucine binding, redundant with the experimental IDA annotation (PMID:12742085). L-leucine is a physiological allosteric activator of GLUD1; accurate regulatory function (non-core). Supporting Evidence: PMID:11032875 L-leucine, at 1.0 mM:, enhanced the activity of the nerve tissue-specific
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a high-throughput affinity-purification interactome (BioPlex). The term is uninformative about GLUD1 molecular function; the recorded partners (GLUD2 paralog, KLHL22) are captured elsewhere. Flagged as over-annotated per curation policy for bare protein binding IPIs.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a large-scale interactome (BioPlex 3.0). Uninformative molecular-function term; flagged as over-annotated.
GO:0005515 protein binding	IPI PMID:37788672 Cryo-EM structure of the KLHL22 E3 ligase bound to an oligom...	MARK AS OVER ANNOTATED	Summary: Protein binding from the cryo-EM structure of the KLHL22 E3 ligase bound to the GDH1 hexamer. Although this is a biologically meaningful interaction (KLHL22/CUL3 ubiquitinates GDH1), the bare protein binding term is uninformative; the specific relationship is documented in the notes and the KLHL22 interaction is retained in UniProt. Flagged as over-annotated. Supporting Evidence: PMID:37788672 ligase mediated the polyubiquitination of GDH1 in vitro
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a multimodal cell-map/interactome study. Uninformative molecular-function term; flagged as over-annotated.
GO:0005739 mitochondrion	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: Immunofluorescence (HPA) localization to mitochondrion. Correct; consistent with the predominant mitochondrial localization. Retained as accurate but non-core relative to mitochondrial matrix.
GO:0004352 L-glutamate dehydrogenase (NAD+) activity	EXP PMID:11254391 Structures of bovine glutamate dehydrogenase complexes eluci...	ACCEPT	Summary: Experimental characterization of GDH catalytic activity and purine regulation from crystallographic/kinetic studies (bovine GDH structures; human HHS mutant kinetics). Supports the NAD(+)-dependent glutamate dehydrogenase activity of GLUD1. Core catalytic function. Supporting Evidence: PMID:11254391 deamination of l-glutamate to 2-oxoglutarate
GO:0004352 L-glutamate dehydrogenase (NAD+) activity	EXP PMID:16023112 Identification of ADP-ribosylation site in human glutamate d...	ACCEPT	Summary: Experimental measurement of purified human GDH activity and its inhibition by ADP-ribosylation. Confirms the NAD(+)-dependent glutamate dehydrogenase activity of GLUD1. Core catalytic function. Supporting Evidence: PMID:16023112 hGDH isozymes were inhibited by up to 75%
GO:0004352 L-glutamate dehydrogenase (NAD+) activity	EXP PMID:16959573 SIRT4 inhibits glutamate dehydrogenase and opposes the effec...	ACCEPT	Summary: Experimental demonstration that GDH activity is regulated (downregulated by SIRT4-mediated ADP-ribosylation). Supports the NAD(+)-dependent glutamate dehydrogenase activity. Core catalytic function. Supporting Evidence: PMID:16959573 downregulate glutamate dehydrogenase (GDH) activity
GO:0004354 L-glutamate dehydrogenase (NADP+) activity	EXP PMID:11032875 Nerve tissue-specific (GLUD2) and housekeeping (GLUD1) human...	ACCEPT	Summary: Experimental kinetic characterization of recombinant human GLUD1-derived GDH, which functions with NADP(+) as well as NAD(+). Supports the NADP(+)-dependent activity, part of the dual-cofactor core function. Supporting Evidence: PMID:11032875 Nonactivated GLUD1 GDH was markedly inhibited
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	KEEP AS NON CORE	Summary: High-throughput mitochondrial-proteome detection. Consistent with the established mitochondrial localization; accurate but non-core relative to mitochondrial matrix.
GO:0042803 protein homodimerization activity	IPI PMID:11903050 Expression, purification and characterization of human gluta...	KEEP AS NON CORE	Summary: Self-interaction annotation. GLUD1 assembles into a homohexamer (a trimer of dimers), so a homo-oligomerization/self-association activity is real, though homodimerization is a slightly imprecise description of the hexameric assembly. The self-association is intrinsic to enzyme assembly rather than a standalone signaling function, so it is kept as non-core. Supporting Evidence: file:human/GLUD1/GLUD1-uniprot.txt Homohexamer (By similarity)
GO:0005739 mitochondrion	IDA PMID:19448744 Human GLUD1 and GLUD2 glutamate dehydrogenase localize to mi...	KEEP AS NON CORE	Summary: Experimental (confocal colocalization with a mitochondrial marker) localization to mitochondrion. Directly supports the predominant mitochondrial localization of GLUD1. Retained as accurate but non-core relative to the matrix term. Supporting Evidence: PMID:19448744 colocalized with the mitochondrial marker DsRed2-Mito
GO:0005783 endoplasmic reticulum	IDA PMID:19448744 Human GLUD1 and GLUD2 glutamate dehydrogenase localize to mi...	KEEP AS NON CORE	Summary: Experimental colocalization showing a minor pool of GLUD1 in the endoplasmic reticulum in addition to mitochondria. Real but minor; not the core site of function. Supporting Evidence: PMID:19448744 part of the protein localizes to the endoplasmic reticulum
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-5688276	ACCEPT	Summary: Reactome traceable-author localization to the mitochondrial matrix (in the context of SIRT4 transferring ADP-ribose to GLUD). This is the specific, correct site of the active enzyme. Core location. Supporting Evidence: PMID:11903050 in the mitochondrial matrix
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-5688289	ACCEPT	Summary: Reactome traceable-author localization to the mitochondrial matrix (SIRT3 deacetylation reaction context). Correct core location of the enzyme. Supporting Evidence: PMID:11903050 in the mitochondrial matrix
GO:0021762 substantia nigra development	HEP PMID:22926577 Quantitative proteomic analysis of human substantia nigra in...	MARK AS OVER ANNOTATED	Summary: Derived from a quantitative proteomics survey of human substantia nigra in neurodegenerative disease (expression-pattern HEP evidence). Mere detection or differential abundance in a brain region does not establish a role in substantia nigra development; this is an over-annotation of GLUD1 function.
GO:0006541 L-glutamine metabolic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence-similarity transfer of a role in glutamine metabolism. GLUD1 does not act directly on glutamine, but it is central to glutamine anaplerosis by producing alpha-ketoglutarate downstream of glutaminase; this places it within the glutamine metabolic network. Kept as accurate but non-core (indirect). Supporting Evidence: file:human/GLUD1/GLUD1-uniprot.txt glutamine anaplerosis by producing alpha-ketoglutarate, an important
GO:0072350 tricarboxylic acid metabolic process	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity transfer of a role in TCA-cycle intermediate metabolism. Accurate: GLUD1 supplies alpha-ketoglutarate, a key TCA intermediate, linking it to the tricarboxylic acid metabolic process (anaplerosis). Core-adjacent process reflecting the enzyme principal metabolic role. Supporting Evidence: file:human/GLUD1/GLUD1-uniprot.txt intermediate in the tricarboxylic acid cycle
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-70589	ACCEPT	Summary: Reactome traceable-author localization to the mitochondrial matrix, annotated on the reverse GDH reaction (alpha-ketoglutarate + NH4+ + NAD(P)H -> glutamate). Correct core location. Supporting Evidence: PMID:11903050 in the mitochondrial matrix
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-70600	ACCEPT	Summary: Reactome traceable-author localization to the mitochondrial matrix, annotated on the forward GDH reaction (glutamate + NAD(P)+ -> alpha-ketoglutarate). Correct core location. Supporting Evidence: PMID:11903050 in the mitochondrial matrix
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838081	ACCEPT	Summary: Reactome traceable-author localization to the mitochondrial matrix (LONP1 degradation of matrix proteins context). Correct core location. Supporting Evidence: PMID:11903050 in the mitochondrial matrix
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838093	ACCEPT	Summary: Reactome traceable-author localization to the mitochondrial matrix (LONP1 binding of matrix proteins context). Correct core location. Supporting Evidence: PMID:11903050 in the mitochondrial matrix
GO:0005515 protein binding	IPI PMID:16959573 SIRT4 inhibits glutamate dehydrogenase and opposes the effec...	MARK AS OVER ANNOTATED	Summary: Protein binding annotation with SIRT4 (Q9Y6E7) as partner. The biologically meaningful relationship is that SIRT4 ADP-ribosylates and inhibits GLUD1; the bare protein binding term is uninformative about the GLUD1 molecular function. Flagged as over-annotated per policy. Supporting Evidence: PMID:16959573 SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate
GO:0070728 L-leucine binding	IDA PMID:12742085 Study of structure-function relationships in human glutamate...	KEEP AS NON CORE	Summary: Experimental (structure-function/mutagenesis) evidence for L-leucine binding, the physiological allosteric activator site. Accurate regulatory-ligand binding function; kept as non-core relative to catalysis. Supporting Evidence: PMID:11032875 L-leucine, at 1.0 mM:, enhanced the activity of the nerve tissue-specific
GO:0005525 GTP binding	IDA PMID:11032875 Nerve tissue-specific (GLUD2) and housekeeping (GLUD1) human...	KEEP AS NON CORE	Summary: Experimental evidence for GTP binding, the major allosteric inhibitor of GLUD1 (nonactivated enzyme inhibited by GTP with IC50 ~0.2 microM). Accurate regulatory-ligand binding function; central to physiology and disease (loss of GTP inhibition causes HHF6) but kept as non-core relative to catalysis. Supporting Evidence: PMID:11032875 Nonactivated GLUD1 GDH was markedly inhibited
GO:0005737 cytoplasm	IDA PMID:18688271 Mitochondrial targeting adaptation of the hominoid-specific ...	KEEP AS NON CORE	Summary: Experimental localization showing GLUD1 in the cytoplasm in addition to mitochondria (in contrast to the mitochondria-specific GLUD2). This is a genuine but minor extramitochondrial pool; not the core site of function. Supporting Evidence: PMID:18688271 GLUD1 localizes to the mitochondria as well as the cytoplasm
GO:0043531 ADP binding	IDA PMID:12742085 Study of structure-function relationships in human glutamate...	ACCEPT	Summary: Experimental (structure-function) evidence for ADP binding, the principal allosteric activator site of GLUD1. ADP binding is core to the activated physiological state of the enzyme. Supporting Evidence: file:human/GLUD1/GLUD1-uniprot.txt Activated by ADP
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, and in the reductive amination direction (alpha-ketoglutarate + NH4+ + NAD(P)H -> glutamate) GLUD1 can synthesize glutamate. Reactome models this reverse reaction (R-HSA-70589). Real capacity, but the physiologically dominant/core direction is oxidative deamination (catabolic); glutamate biosynthesis is kept as non-core. Supporting Evidence: file:human/GLUD1/GLUD1-uniprot.txt Reaction=L-glutamate + NAD(+) + H2O = 2-oxoglutarate
GO:0004352 L-glutamate dehydrogenase (NAD+) activity	IDA PMID:11903050 Expression, purification and characterization of human gluta...	ACCEPT	Summary: Direct experimental characterization of purified recombinant human GDH (wild-type and allosteric-regulatory mutants), confirming NAD(+)-dependent glutamate dehydrogenase activity. Core catalytic function. Supporting Evidence: PMID:11903050 catalyses the reversible oxidative deamination of l-glutamate to 2-oxoglutarate in the mitochondrial matrix
GO:0004353 L-glutamate dehydrogenase [NAD(P)+] activity	IDA PMID:11032875 Nerve tissue-specific (GLUD2) and housekeeping (GLUD1) human...	ACCEPT	Summary: Direct experimental evidence for the dual-cofactor [NAD(P)+] glutamate dehydrogenase activity of human GLUD1-derived GDH. This is the single most representative molecular function of the gene. Core catalytic function. Supporting Evidence: PMID:11254391 only animal GDH utilizes
GO:0006538 L-glutamate catabolic process	IDA PMID:11032875 Nerve tissue-specific (GLUD2) and housekeeping (GLUD1) human...	ACCEPT	Summary: Direct experimental support for GLUD1 role in glutamate catabolism (oxidative deamination). Core biological process. Supporting Evidence: PMID:11903050 catalyses the reversible oxidative deamination of l-glutamate to 2-oxoglutarate in the mitochondrial matrix
GO:0032024 positive regulation of insulin secretion	IMP PMID:11502802 Acute insulin responses to leucine in children with the hype...	KEEP AS NON CORE	Summary: Clinical/mutation evidence that GLUD1 activity promotes insulin secretion: gain-of-function GLUD1 mutations (loss of GTP inhibition) cause exaggerated leucine-stimulated insulin release in the hyperinsulinism/hyperammonemia syndrome. This is a genuine, physiologically and clinically important role in pancreatic beta-cells, but it is a downstream, tissue-specific function rather than the enzyme core catalytic role. Kept as non-core. Supporting Evidence: PMID:11502802 syndrome by desensitizing glutamate dehydrogenase to allosteric inhibition by
GO:0070403 NAD+ binding	IDA PMID:12193607 Importance of glutamate 279 for the coenzyme binding of huma...	KEEP AS NON CORE	Summary: Direct experimental identification of the NAD(+) coenzyme-binding site (photoaffinity labeling and mutagenesis of Glu279). NAD(+) binding is intrinsic to catalysis; a genuine cofactor-binding function, kept as non-core relative to the catalytic activity term it supports. Supporting Evidence: PMID:12193607 Glu(279) plays an important role for efficient binding of NAD(+) to human
GO:0004352 L-glutamate dehydrogenase (NAD+) activity	IDA PMID:15578726 Molecular basis of human glutamate dehydrogenase regulation ...	ACCEPT	Summary: Direct experimental characterization of recombinant human GLUD1-derived GDH activity and its regulation. Confirms NAD(+)-dependent glutamate dehydrogenase activity. Core catalytic function. Supporting Evidence: PMID:15578726 GTP potently inhibits GLUD1-derived GDH
GO:0005739 mitochondrion	IDA PMID:15578726 Molecular basis of human glutamate dehydrogenase regulation ...	KEEP AS NON CORE	Summary: Experimental (GFP-fusion imaging) localization of GLUD1 to mitochondria, colocalizing with a mitochondrial marker. Supports the predominant mitochondrial localization; kept as non-core relative to mitochondrial matrix. Supporting Evidence: PMID:15578726 revealed a GFP fluorescence pattern nearly identical to that of the
GO:0006538 L-glutamate catabolic process	IDA PMID:6121377 Abnormal glutamate metabolism in an adult-onset degenerative...	ACCEPT	Summary: Human evidence linking GDH deficiency to impaired glutamate catabolism (elevated plasma glutamate, reduced alpha-ketoglutarate; decreased glutamate catabolism in patients with partial GDH deficiency). Supports the core glutamate catabolic process. Supporting Evidence: PMID:6121377 Decreased glutamate

Gene Description

Existing Annotations Review

Core Functions

ADP binding: binds ADP at a defined allosteric site, which activates the enzyme (and sensitizes it to L-leucine). ADP binding drives GLUD1 into its catalytically active state under conditions of high ADP:ATP ratio, integrating enzyme activity with cellular energy charge.

References

📚 Additional Documentation

Notes

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