GLS2

Summary

GLS2 (glutaminase 2, HGNC:29570) is a protein-coding gene on chromosome 12q13.3, encoding Glutaminase liver isoform, mitochondrial (Q9UI32). Plays an important role in the regulation of glutamine catabolism.

The protein encoded by this gene is a mitochondrial phosphate-activated glutaminase that catalyzes the hydrolysis of glutamine to stoichiometric amounts of glutamate and ammonia. Originally thought to be liver-specific, this protein has been found in other tissues as well. Alternative splicing results in multiple transcript variants that encode different isoforms.

Source: NCBI Gene 27165 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 72 total
• Phenotypes (HPO): 32
• Druggable target: yes
• MANE Select transcript: NM_013267

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29570
Approved symbol	GLS2
Name	glutaminase 2
Location	12q13.3
Locus type	gene with protein product
Status	Approved
Aliases	GA, GLS, LGA, hLGA
Ensembl gene	ENSG00000135423
Ensembl biotype	protein_coding
OMIM	606365
Entrez	27165

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 20 protein_coding, 6 nonsense_mediated_decay, 5 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000311966, ENST00000390288, ENST00000424141, ENST00000461077, ENST00000471282, ENST00000476991, ENST00000479952, ENST00000483347, ENST00000486433, ENST00000486896, ENST00000491880, ENST00000494345, ENST00000494474, ENST00000496006, ENST00000873336, ENST00000873337, ENST00000873338, ENST00000873339, ENST00000873340, ENST00000873341, ENST00000873342, ENST00000873343, ENST00000873344, ENST00000873345, ENST00000873346, ENST00000873347, ENST00000873348, ENST00000873349, ENST00000873350, ENST00000873351, ENST00000873352, ENST00000873353

RefSeq mRNA: 4 — MANE Select: NM_013267 NM_001280796, NM_001280797, NM_001280798, NM_013267

CCDS: CCDS8921

Canonical transcript exons

ENST00000311966 — 18 exons

Exon	Start	End
ENSE00003489915	56479052	56479181
ENSE00003501874	56471773	56471836
ENSE00003504621	56477933	56478096
ENSE00003526084	56474544	56474720
ENSE00003535305	56475945	56475977
ENSE00003559164	56473228	56473320
ENSE00003559334	56475044	56475110
ENSE00003560721	56477660	56477718
ENSE00003564728	56470952	56471643
ENSE00003616039	56474846	56474896
ENSE00003637291	56472690	56472751
ENSE00003651487	56480288	56480387
ENSE00003654999	56473463	56473594
ENSE00003661813	56478183	56478262
ENSE00003662987	56479780	56479901
ENSE00003686897	56472119	56472195
ENSE00003691028	56475624	56475682
ENSE00003850471	56487937	56488161

Expression profiles

Bgee: expression breadth ubiquitous, 222 present calls, max score 96.68.

FANTOM5 (CAGE): breadth broad, TPM avg 3.8617 / max 282.0705, expressed in 624 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131538	1.0933	400
131534	0.9093	289
131533	0.8622	274
131532	0.7856	241
131536	0.1070	20
131531	0.0379	19
131537	0.0322	11
131530	0.0155	8
131529	0.0150	6
131528	0.0038	2

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	96.68	gold quality
cerebellar hemisphere	UBERON:0002245	95.11	gold quality
cerebellar cortex	UBERON:0002129	95.01	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.92	gold quality
liver	UBERON:0002107	94.45	gold quality
cerebellum	UBERON:0002037	94.24	gold quality
body of pancreas	UBERON:0001150	93.87	gold quality
right frontal lobe	UBERON:0002810	91.29	gold quality
oocyte	CL:0000023	90.15	gold quality
primary visual cortex	UBERON:0002436	90.14	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.05	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.83	gold quality
middle temporal gyrus	UBERON:0002771	89.80	gold quality
buccal mucosa cell	CL:0002336	89.46	gold quality
Brodmann (1909) area 10	UBERON:0013541	89.30	gold quality
prefrontal cortex	UBERON:0000451	88.92	gold quality
orbitofrontal cortex	UBERON:0004167	88.90	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	88.87	gold quality
frontal cortex	UBERON:0001870	87.74	gold quality
pituitary gland	UBERON:0000007	87.69	gold quality
cingulate cortex	UBERON:0003027	87.41	gold quality
anterior cingulate cortex	UBERON:0009835	87.38	gold quality
pancreas	UBERON:0001264	87.03	gold quality
neocortex	UBERON:0001950	86.94	gold quality
Brodmann (1909) area 23	UBERON:0013554	86.88	gold quality
adenohypophysis	UBERON:0002196	86.46	gold quality
nucleus accumbens	UBERON:0001882	86.24	gold quality
Brodmann (1909) area 46	UBERON:0006483	85.91	gold quality
occipital lobe	UBERON:0002021	85.72	gold quality
cerebral cortex	UBERON:0000956	85.45	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.75

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, COQ7, GATA3, HNF1A, ISL1, SP1, TP53, TP63

miRNA regulators (miRDB)

43 targeting GLS2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-4524A-5P	99.57	71.73	1193
HSA-MIR-4524B-5P	99.57	71.68	1195
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-4796-5P	99.34	70.06	810
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-4270	99.02	66.26	1987

Literature-anchored findings (GeneRIF, showing 35)

• results show L-type glutaminase is expressed in the brain with a nuclear localization and that this nuclear enzyme is catalytically active and displays kinetic properties different from both liver and kidney glutaminases (PMID:12163477)
• Data describe the characterization of the human liver-type glutaminase (hLGA) gene. (PMID:12444921)
• High levels of glutamate were produced by monocyte-derived macrophages infected with HIV-1 strains and inhibited by a glutaminase inhibitor and AZT thus implicating a glutamate-generating enzyme such as phosphate-activated mitochondrial glutaminase (PMID:14675161)
• K glutaminase isoform is up-regulated with increased rates of proliferation in cancer cells, whereas prevalence of the L isoform seems to be related with resting or quiescent cell states (PMID:15496140)
• These data implicate mitochondrial glutaminase in the induction of glutamate-mediated neuronal apoptosis during HIV-associated dementia, and provides a possible therapeutic strategy for HAD treatment. (PMID:18088378)
• presence of LGA mRNA in transfected glioma cells coincided with depression of basic physiological parameters: Cell migration, proliferation, and survival as assessed with colony formation assay and the mitochondrial activity test (PMID:19062176)
• Phosphate-activated glutaminase (GLS2) is a p53-inducible regulator of glutamine metabolism and reactive oxygen species (PMID:20351271)
• as a unique p53 target gene, GLS2 is a mediator of p53’s role in energy metabolism and antioxidant defense, which can contribute to its role in tumor suppression (PMID:20378837)
• GLS2 is resistant to BPTES; GLS1 mutants created reflecting differences between GLS2 and GLS1 sequence in region of BPTES binding; mutant proteins lost inhibition by BPTES; amino acid sequence alignment GLS2 versus GLS1 (PMID:22049910)
• Study demonstrated expression of alternative transcripts of the mammalian Gls2 gene. Transcriptional mechanisms giving rise to GLS2 variants and isolation of novel GLS2 transcripts in human, rat and mouse are presented. (PMID:22679499)
• LGA circumvents, by an as yet unknown route, the most common mechanism of O6-methylguanine-DNA methyltransferase (MGMT) gene silencing. (PMID:22888977)
• GLS2 is a bona fide TAp63 target gene. (PMID:23574722)
• The present study was to investigate the potent effect of GLS2 on radioresistance of cervical carcinoma. (PMID:23954443)
• combination of negative modulation of glutaminase isoforms arising from GLS gene with the introduction of the GLS2 gene product, GAB, may in the future provide a useful means to curb glioblastoma growth in situ (PMID:24096582)
• GLS2 is acting, at least in part, downstream of p73 in neuronal differentiation and highlight a possible role of p73 in regulating neurotransmitter synthesis. (PMID:24121663)
• Silencing GLS or overexpressing GLS2 induces growth inhibition in glioma cell lines. (PMID:24276018)
• Epigenetic silencing of Gls2 via promoter hypermethylation is common in human liver and colon cancers. (PMID:24330717)
• GLS2 expression is significantly decreased in hepatocellular carcinoma. (PMID:24797434)
• Phosphate-activated glutaminase and GAD65/67 concentrations are compared in Alzheimer’s disease cerebellum versus normal cerebellum controls (PMID:24950944)
• GABAergic neurons and astrocytes express Gls and Gls2 isoenzymes in nucleus and mitochondria, in addition to glutamatergic neurons (PMID:25297978)
• This study assessed the relation of GLS2 downregulation in glioblastoma cells to its methylation and TP53 status. Aberrant methylation of CpG islands, appear to contribute to silencing of GLS2 in glioblastoma cells by a mechanism bypassing TP53 mutations. (PMID:26258493)
• IDO, through GCN2 kinase activation, downregulates the levels of TCRcomplex tchain and cMyc, resulting in the suppression of Tcell proliferation and a reduction in the levels of LDHA and GLS2 (PMID:26647830)
• As a p53 target, GLS2 mediates p53’s function in metastasis suppression through inhibiting Rac1. (PMID:26751560)
• Cox multivariate regression analysis demonstrated that DUOX1, GLS2, FBP1 and age were independent risk factors for the prognosis of HCC patients after surgery (PMID:27079415)
• observe that while miR-23 is capable of down-regulating the shortened KGA 3’UTR, it has only minor impact on the full-length KGA 3’UTR, demonstrating that additional potent negative regulation of GLS expression exists beyond this single microRNA targeting site (PMID:27095025)
• Non-glutaminolysis function of GLS2 inhibits migration and invasion of hepatocellular carcinoma cells by repressing the epithelial-mesenchymal transition via the Dicer-miR-34a-Snail axis. (PMID:27725225)
• the crystal structure of full-length KGA and present a small-angle X-ray scattering model for full-length GLS2. These structures explain these proteins’ compromised ability to assemble into catalytically active supra-tetrameric filaments, as previously shown for GAC. (PMID:28526749)
• Gene-based analysis of the 342 genes in the replication sample using SKAT-O identified one gene, GLS2, significantly associated with complicated Staphylococcus aureus bacteremia(p = 1.2 x 10-4) after Bonferroni correction. The strongest association across all 10,931 variants in the replication sample was with rs2657878 in GLS2 (p = 5 x 10-4). This variant is strongly correlated with a missense variant (rs2657879) (PMID:30289878)
• Study verified that several breast cancer cell lines express endogenous GLS2 and GLS2 expression is linked to enhanced in vitro cell migration and invasion, mesenchymal markers and in vivo lung metastasis. GLS2 amplification or overexpression is linked to worse survival prognosis in breast cancer. Data establish an unforeseen role of GLS2 in sustaining tumor proliferation and underlying metastasis in breast cancer. (PMID:31541193)
• Liver-Type Glutaminase GLS2 Is a Druggable Metabolic Node in Luminal-Subtype Breast Cancer. (PMID:31577957)
• Nuclear Translocation of Glutaminase GLS2 in Human Cancer Cells Associates with Proliferation Arrest and Differentiation. (PMID:32042057)
• Upregulation of glutaminase 2 and neutrophil cytosolic factor 2 is associated with the poor prognosis of glioblastoma. (PMID:33179520)
• Glutaminase isoforms expression switches microRNA levels and oxidative status in glioblastoma cells. (PMID:33610185)
• Structure and activation mechanism of the human liver-type glutaminase GLS2. (PMID:33746066)
• GLS2 Is a Tumor Suppressor and a Regulator of Ferroptosis in Hepatocellular Carcinoma. (PMID:35895807)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	gls2b	ENSDARG00000002917
danio_rerio	gls2a	ENSDARG00000069095
mus_musculus	Gls2	ENSMUSG00000044005
rattus_norvegicus	Gls2	ENSRNOG00000031612
drosophila_melanogaster	GLS	FBGN0261625
caenorhabditis_elegans		WBGENE00007480
caenorhabditis_elegans		WBGENE00008435
caenorhabditis_elegans	glna-3	WBGENE00009271

Paralogs (1): GLS (ENSG00000115419)

Protein

Protein identifiers

Glutaminase liver isoform, mitochondrial — Q9UI32 (reviewed: Q9UI32)

Alternative names: L-glutaminase, L-glutamine amidohydrolase

All UniProt accessions (7): A8K0A6, C9J3Q2, Q9UI32, F8WBC9, F8WBL8, F8WEU7, G5E9X4

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in the regulation of glutamine catabolism. Promotes mitochondrial respiration and increases ATP generation in cells by catalyzing the synthesis of glutamate and alpha-ketoglutarate. Increases cellular anti-oxidant function via NADH and glutathione production. May play a role in preventing tumor proliferation.

Subunit / interactions. Homotetramer, dimer of dimers. Does not assemble into higher oligomers. Interacts with the PDZ domain of the syntrophin SNTA1. Interacts with the PDZ domain of TAX1BP3.

Subcellular location. Mitochondrion.

Tissue specificity. Highly expressed in liver. Expressed in brain and pancreas. Not observed in heart, placenta, lung, skeletal muscle and kidney. Expression is significantly reduced in hepatocellular carcinomas.

Induction. Up-regulated by P53 (at protein and mRNA level) under both stressed and non-stressed conditions.

Similarity. Belongs to the glutaminase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UI32-1	1	yes
Q9UI32-2	2

RefSeq proteins (4): NP_001267725, NP_001267726, NP_001267727, NP_037399* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR012338	Beta-lactam/transpept-like	Homologous_superfamily
IPR015868	Glutaminase	Family
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR041541	Glutaminase_EF-hand	Domain

Pfam: PF04960, PF12796, PF17959

Catalyzed reactions (Rhea), 1 shown:

• L-glutamine + H2O = L-glutamate + NH4(+) (RHEA:15889)

UniProt features (61 total): helix 21, strand 8, binding site 7, turn 7, sequence conflict 5, modified residue 4, splice variant 2, repeat 2, transit peptide 1, chain 1, sequence variant 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4BQM	X-RAY DIFFRACTION	2.18
5U0K	X-RAY DIFFRACTION	2.55
8SZL	ELECTRON MICROSCOPY	3.12
8T0Z	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UI32-F1	85.66	0.67

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (7): 347; 399; 417; 219; 268; 314; 321

Post-translational modifications (4): 253, 279, 284, 329

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-210500	Glutamate Neurotransmitter Release Cycle
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-8964539	Glutamate and glutamine metabolism

MSigDB gene sets: 530 (showing top): HORIUCHI_WTAP_TARGETS_DN, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_BEHAVIOR, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_REGULATION_OF_RESPIRATORY_SYSTEM_PROCESS, GOBP_GLUTAMATE_METABOLIC_PROCESS, GOBP_SUCKLING_BEHAVIOR, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_RESPIRATORY_SYSTEM_PROCESS, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS

GO Biological Process (6): amino acid metabolic process (GO:0006520), obsolete glutamate biosynthetic process (GO:0006537), L-glutamine catabolic process (GO:0006543), regulation of apoptotic process (GO:0042981), reactive oxygen species metabolic process (GO:0072593), L-glutamine metabolic process (GO:0006541)

GO Molecular Function (3): glutaminase activity (GO:0004359), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Neurotransmitter release cycle	1
Transcriptional Regulation by TP53	1
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
primary metabolic process	1
L-glutamine metabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
apoptotic process	1
regulation of programmed cell death	1
metabolic process	1
L-amino acid metabolic process	1
proteinogenic amino acid metabolic process	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1466 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GLS2	SLC1A5	Q15758	830
GLS2	GLUL	P15104	714
GLS2	TIGAR	Q9NQ88	696
GLS2	CXCR1	P25024	680
GLS2	GLUD1	P00367	666
GLS2	SCO2	O43819	653
GLS2	ASS1	P00966	614
GLS2	H6PD	O95479	603
GLS2	SLC7A11	Q9UPY5	592
GLS2	TP53	P04637	576
GLS2	SAT1	P21673	575
GLS2	SLC38A2	Q96QD8	571
GLS2	ALDH4A1	P30038	543
GLS2	CCR2	P41597	525
GLS2	ACSL4	O60488	521

IntAct

10 interactions, top by confidence:

A	B	Type	Score
GRB2	WIPF3	psi-mi:“MI:0914”(association)	0.730
HIP1	GLS2	psi-mi:“MI:0915”(physical association)	0.670
GLS2	HIP1	psi-mi:“MI:0914”(association)	0.670
XAF1	GLS2	psi-mi:“MI:0915”(physical association)	0.560
GRHPR	GLS2	psi-mi:“MI:0915”(physical association)	0.370
GLS2	HIP1	psi-mi:“MI:0915”(physical association)	0.000
GLS2	XAF1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (17): GLS2 (Reconstituted Complex), GLS2 (Co-localization), GLS2 (Co-localization), GLS2 (Co-localization), GLS2 (Co-localization), GLS2 (Two-hybrid), GLS2 (Two-hybrid), GLS2 (Affinity Capture-MS), GLS2 (Affinity Capture-MS), GLS2 (Protein-RNA), GLS (Affinity Capture-MS), HIP1R (Affinity Capture-MS), HIP1 (Affinity Capture-MS), GLS2 (Affinity Capture-MS), GLS2 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A2TLM1, B4G0F3, B8BKI7, B9N1F9, B9SQI7, C1BJB1, C6JS30, D2XV59, E0CSI1, E9Q4Z2, F4JGR5, O00178, O00763, O04059, O08582, O19069, P0DPI2, P11029, P11497, P13086, P19356, P21343, P22907, P28492, P47968, P49247, P53597, Q13085, Q28559, Q2R483, Q3T186, Q571F8, Q58DC5, Q58DR8, Q5I0K3, Q5NAY4, Q5R8Q7, Q5SWU9, Q5XGS8, Q5ZHY5

Diamond homologs: A0JNU3, A1RX40, A4YHH3, A5UK11, A6VGK5, B0R6H4, C3MPS1, C3MYR5, C3N5E7, C3NE01, C3NHQ2, C4KH13, O26802, O59132, O88202, P0A962, P0A963, P26900, P61400, Q46GJ6, Q571F8, Q5JI77, Q5JIW4, Q60331, Q653P0, Q86U10, Q8TZE8, Q8U0X0, Q97ZH5, Q9HP20, Q9M8S6, Q9U518, Q9UI32, Q9V0T9, Q9Y9T8, A0KUF0, A0PTH3, A3D705, A4FAB4, A4IPX2

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
GLS2	“down-regulates quantity”	glutamine	“chemical modification”
GLS2	“up-regulates quantity”	L-glutamate(1-)	“chemical modification”
GATA3	“up-regulates quantity by expression”	GLS2	“transcriptional regulation”
TP53	“up-regulates quantity by expression”	GLS2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

72 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	56
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

6061 predictions. Top by Δscore:

Variant	Effect	Δscore
12:56471639:CCCAC:C	acceptor_gain	1.0000
12:56471640:CCAC:C	acceptor_gain	1.0000
12:56471640:CCACC:C	acceptor_gain	1.0000
12:56471641:CAC:C	acceptor_gain	1.0000
12:56471641:CACC:C	acceptor_gain	1.0000
12:56471644:CTG:C	acceptor_loss	1.0000
12:56472106:AAC:A	donor_gain	1.0000
12:56473321:C:CC	acceptor_gain	1.0000
12:56473327:T:C	acceptor_gain	1.0000
12:56473327:T:TC	acceptor_gain	1.0000
12:56473459:TCACC:T	donor_loss	1.0000
12:56473460:CA:C	donor_loss	1.0000
12:56473461:A:AC	donor_gain	1.0000
12:56473462:C:CC	donor_gain	1.0000
12:56473462:CCTGG:C	donor_gain	1.0000
12:56474542:A:AC	donor_gain	1.0000
12:56474543:C:CC	donor_gain	1.0000
12:56474716:CACAG:C	acceptor_gain	1.0000
12:56474717:ACAG:A	acceptor_gain	1.0000
12:56474718:CAG:C	acceptor_gain	1.0000
12:56474718:CAGC:C	acceptor_gain	1.0000
12:56474719:AG:A	acceptor_gain	1.0000
12:56474720:GC:G	acceptor_loss	1.0000
12:56474721:C:CC	acceptor_gain	1.0000
12:56474723:A:C	acceptor_gain	1.0000
12:56474840:TCTTA:T	donor_loss	1.0000
12:56474841:CTTA:C	donor_loss	1.0000
12:56474842:TTAC:T	donor_loss	1.0000
12:56474843:TACC:T	donor_loss	1.0000
12:56474895:CA:C	acceptor_gain	1.0000

AlphaMissense

3972 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:56477705:G:C	N264K	1.000
12:56477705:G:T	N264K	1.000
12:56474593:A:G	L392P	0.999
12:56474595:G:C	S391R	0.999
12:56474595:G:T	S391R	0.999
12:56474597:T:G	S391R	0.999
12:56474599:A:G	L390P	0.999
12:56474656:C:T	G371E	0.999
12:56474657:C:A	G371W	0.999
12:56474674:G:T	A365D	0.999
12:56475057:A:G	L328P	0.999
12:56475066:C:T	G325D	0.999
12:56475072:G:T	A323D	0.999
12:56477667:A:G	L277P	0.999
12:56477688:C:T	G270D	0.999
12:56477693:A:C	N268K	0.999
12:56477693:A:T	N268K	0.999
12:56478031:G:T	A227D	0.999
12:56478183:C:G	R205P	0.999
12:56478189:C:T	G203D	0.999
12:56472130:G:T	A526D	0.998
12:56472148:C:G	R520P	0.998
12:56472149:G:T	R520S	0.998
12:56472720:G:T	A494D	0.998
12:56473530:C:T	G430E	0.998
12:56473531:C:G	G430R	0.998
12:56473531:C:T	G430R	0.998
12:56473581:G:T	A413D	0.998
12:56474547:G:C	F407L	0.998
12:56474547:G:T	F407L	0.998

dbSNP variants (sampled 300 via entrez): RS1000094799 (12:56475547 C>A,G,T), RS1000265411 (12:56472948 C>A,T), RS1000318992 (12:56472557 A>C,G), RS1000755087 (12:56481847 C>A,T), RS1000824490 (12:56480464 T>A), RS1001140688 (12:56486193 C>G), RS1001356372 (12:56485266 T>C), RS1002031619 (12:56481245 G>A,T), RS1002101084 (12:56478956 C>A,G), RS1002382395 (12:56481482 A>G), RS1002486141 (12:56473853 C>T), RS1002756734 (12:56484799 T>C), RS1002836444 (12:56481408 A>C), RS1003058209 (12:56477533 C>T), RS1003160316 (12:56470645 A>C)

Disease associations

OMIM: gene MIM:606365 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000713	Agitation
HP:0000750	Delayed speech and language development
HP:0000817	Reduced eye contact
HP:0000962	Hyperkeratosis
HP:0001036	Parakeratosis
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001482	Subcutaneous nodule
HP:0002073	Progressive cerebellar ataxia
HP:0002093	Respiratory insufficiency
HP:0002171	Gliosis
HP:0002188	Delayed CNS myelination
HP:0002194	Delayed gross motor development
HP:0002373	Febrile seizure (within the age range of 3 months to 6 years)
HP:0002751	Kyphoscoliosis
HP:0002878	Respiratory failure
HP:0003217	Hyperglutaminemia
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0005484	Secondary microcephaly
HP:0007305	CNS demyelination
HP:0008936	Axial hypotonia
HP:0009879	Simplified gyral pattern
HP:0010851	EEG with burst suppression
HP:0011463	Childhood onset
HP:0012196	Cheyne-Stokes respiration

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST001217_33	Metabolic traits	3.000000e-17
GCST001391_13	Metabolite levels	2.000000e-35
GCST001639_2	Metabolite levels	7.000000e-30
GCST002115_16	Axial length	4.000000e-07
GCST006249_86	Serum metabolite levels	3.000000e-13
GCST007382_10	Plasma free amino acid levels (adjusted for twenty other PFAAs)	2.000000e-18
GCST007382_12	Plasma free amino acid levels (adjusted for twenty other PFAAs)	2.000000e-18
GCST007383_45	Plasma free amino acid levels (adjusted for one other PFAA)	1.000000e-13
GCST007383_46	Plasma free amino acid levels (adjusted for one other PFAA)	2.000000e-13
GCST007383_47	Plasma free amino acid levels (adjusted for one other PFAA)	4.000000e-13
GCST007383_49	Plasma free amino acid levels (adjusted for one other PFAA)	2.000000e-11
GCST007383_50	Plasma free amino acid levels (adjusted for one other PFAA)	3.000000e-11
GCST007385_1	Plasma free amino acid levels	3.000000e-11
GCST007638_44	Glycine levels	2.000000e-08
GCST008745_1	Estimated glomerular filtration rate in non-diabetics	9.000000e-10
GCST008747_158	Estimated glomerular filtration rate	7.000000e-06
GCST009028_12	Adverse response to drug	2.000000e-07
GCST009240_69	Serum metabolite levels (CMS)	7.000000e-36
GCST009242_311	Serum metabolite levels	5.000000e-33
GCST012232_21	Lipoprotein (a) levels	2.000000e-08

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004725	metabolite measurement
EFO:0004723	coronary artery calcification
EFO:0005318	axial length measurement
EFO:0005134	amino acid measurement
EFO:0009768	glutamine measurement
EFO:0009767	glycine measurement
EFO:0009658	adverse effect
EFO:0006925	lipoprotein A measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4105730 (SINGLE PROTEIN), CHEMBL4106183 (PROTEIN FAMILY)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

17 potent at pChembl≥5 of 20 total, top 17 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.99	IC50	102	nM	CHEMBL4080388
6.58	IC50	261	nM	CHEMBL4090687
6.58	IC50	260	nM	CHEMBL4452796
6.57	IC50	269	nM	CHEMBL4082885
6.55	IC50	280	nM	CHEMBL4552664
6.54	IC50	290	nM	CHEMBL4472618
6.10	IC50	787	nM	CHEMBL4061000
5.99	IC50	1031	nM	CHEMBL4072390
5.93	IC50	1185	nM	CHEMBL4065595
5.92	IC50	1188	nM	CHEMBL4098413
5.92	IC50	1189	nM	CHEMBL4065936
5.91	IC50	1244	nM	CHEMBL4087349
5.76	IC50	1716	nM	CHEMBL4099331
5.67	IC50	2142	nM	CHEMBL4069677
5.42	IC50	3778	nM	CHEMBL4100814
5.38	IC50	4188	nM	CHEMBL4074218
5.24	IC50	5725	nM	CHEMBL4087025

PubChem BioAssay actives

17 with measured affinity, of 58 total; 17 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(5Z)-5-[[4-[4-[3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2,5-dithiophen-2-ylpyrrol-1-yl]phenyl]phenyl]methylidene]-1,3-thiazolidine-2,4-dione	1445483: Inhibition of recombinant human His-tagged GAB (P56 to V602 residues) expressed in Escherichia coli C41(DE3)pLysS using glutamine as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins by glutamate dehydrogenase coupled enzyme assay	ic50	0.1020	uM
[(2R)-1-(3,6-dihydroxy-5-methoxycyclohexa-1,4-dien-1-yl)tridecan-2-yl] acetate	1622897: Inhibition of GLS2 (unknown origin)	ic50	0.2600	uM
(5Z)-5-[[4-[4-[3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2,5-diphenylpyrrol-1-yl]phenyl]phenyl]methylidene]-1,3-thiazolidine-2,4-dione	1445483: Inhibition of recombinant human His-tagged GAB (P56 to V602 residues) expressed in Escherichia coli C41(DE3)pLysS using glutamine as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins by glutamate dehydrogenase coupled enzyme assay	ic50	0.2610	uM
(5Z)-5-[[4-[4-[3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2,5-dithiophen-2-ylpyrrol-1-yl]-2-methoxyphenyl]phenyl]methylidene]-1,3-thiazolidine-2,4-dione	1445483: Inhibition of recombinant human His-tagged GAB (P56 to V602 residues) expressed in Escherichia coli C41(DE3)pLysS using glutamine as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins by glutamate dehydrogenase coupled enzyme assay	ic50	0.2690	uM
1-(5-methoxy-3,6-dioxocyclohexa-1,4-dien-1-yl)pentadecan-2-yl acetate	1622897: Inhibition of GLS2 (unknown origin)	ic50	0.2800	uM
[(2R)-1-(5-methoxy-3,6-dioxocyclohexa-1,4-dien-1-yl)tridecan-2-yl] acetate	1622897: Inhibition of GLS2 (unknown origin)	ic50	0.2900	uM
(5Z)-5-[[4-[4-[3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2,5-diphenylpyrrol-1-yl]-2-methoxyphenyl]phenyl]methylidene]-1,3-thiazolidine-2,4-dione	1445483: Inhibition of recombinant human His-tagged GAB (P56 to V602 residues) expressed in Escherichia coli C41(DE3)pLysS using glutamine as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins by glutamate dehydrogenase coupled enzyme assay	ic50	0.7870	uM
(5Z)-5-[[4-[4-[3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2,5-dimethylpyrrol-1-yl]phenyl]-2-ethylphenyl]methylidene]-1,3-thiazolidine-2,4-dione	1445483: Inhibition of recombinant human His-tagged GAB (P56 to V602 residues) expressed in Escherichia coli C41(DE3)pLysS using glutamine as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins by glutamate dehydrogenase coupled enzyme assay	ic50	1.0310	uM
5-[3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2,5-dimethylpyrrol-1-yl]-2-[4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-3-ethylphenyl]benzonitrile	1445483: Inhibition of recombinant human His-tagged GAB (P56 to V602 residues) expressed in Escherichia coli C41(DE3)pLysS using glutamine as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins by glutamate dehydrogenase coupled enzyme assay	ic50	1.1850	uM
(5Z)-5-[[4-[4-[3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2,5-dimethylpyrrol-1-yl]phenyl]phenyl]methylidene]-1,3-thiazolidine-2,4-dione	1445483: Inhibition of recombinant human His-tagged GAB (P56 to V602 residues) expressed in Escherichia coli C41(DE3)pLysS using glutamine as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins by glutamate dehydrogenase coupled enzyme assay	ic50	1.1880	uM
(5Z)-5-[[4-[4-[3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2,5-dimethylpyrrol-1-yl]-2-methoxyphenyl]-2-ethylphenyl]methylidene]-1,3-thiazolidine-2,4-dione	1445483: Inhibition of recombinant human His-tagged GAB (P56 to V602 residues) expressed in Escherichia coli C41(DE3)pLysS using glutamine as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins by glutamate dehydrogenase coupled enzyme assay	ic50	1.1890	uM
(5Z)-5-[[4-[4-[3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2,5-diphenylpyrrol-1-yl]phenyl]-2-ethylphenyl]methylidene]-1,3-thiazolidine-2,4-dione	1445483: Inhibition of recombinant human His-tagged GAB (P56 to V602 residues) expressed in Escherichia coli C41(DE3)pLysS using glutamine as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins by glutamate dehydrogenase coupled enzyme assay	ic50	1.2440	uM
(5Z)-5-[[4-[4-[3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2,5-dithiophen-2-ylpyrrol-1-yl]phenyl]-2-ethylphenyl]methylidene]-1,3-thiazolidine-2,4-dione	1445483: Inhibition of recombinant human His-tagged GAB (P56 to V602 residues) expressed in Escherichia coli C41(DE3)pLysS using glutamine as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins by glutamate dehydrogenase coupled enzyme assay	ic50	1.7160	uM
(5Z)-5-[[4-[4-[3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2,5-dimethylpyrrol-1-yl]-2-methoxyphenyl]phenyl]methylidene]-1,3-thiazolidine-2,4-dione	1445483: Inhibition of recombinant human His-tagged GAB (P56 to V602 residues) expressed in Escherichia coli C41(DE3)pLysS using glutamine as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins by glutamate dehydrogenase coupled enzyme assay	ic50	2.1420	uM
(5Z)-5-[[1-(4-bromophenyl)-2,5-dithiophen-2-ylpyrrol-3-yl]methylidene]-1,3-thiazolidine-2,4-dione	1445483: Inhibition of recombinant human His-tagged GAB (P56 to V602 residues) expressed in Escherichia coli C41(DE3)pLysS using glutamine as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins by glutamate dehydrogenase coupled enzyme assay	ic50	3.7780	uM
(5Z)-5-[[2-chloro-4-[4-[3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2,5-dimethylpyrrol-1-yl]phenyl]phenyl]methylidene]-1,3-thiazolidine-2,4-dione	1445483: Inhibition of recombinant human His-tagged GAB (P56 to V602 residues) expressed in Escherichia coli C41(DE3)pLysS using glutamine as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins by glutamate dehydrogenase coupled enzyme assay	ic50	4.1880	uM
(5Z)-5-[[4-[4-[3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2,5-dimethylpyrrol-1-yl]-2-hydroxyphenyl]phenyl]methylidene]-1,3-thiazolidine-2,4-dione	1445483: Inhibition of recombinant human His-tagged GAB (P56 to V602 residues) expressed in Escherichia coli C41(DE3)pLysS using glutamine as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins by glutamate dehydrogenase coupled enzyme assay	ic50	5.7250	uM

CTD chemical–gene interactions

46 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression, increases methylation	6
Aflatoxin B1	affects expression, decreases methylation, increases expression	5
Acetaminophen	increases expression, decreases expression	3
entinostat	increases expression, affects cotreatment	2
Resveratrol	affects cotreatment, decreases expression, increases expression	2
Cisplatin	increases expression, decreases response to substance	2
Doxorubicin	increases expression	2
Estradiol	affects cotreatment, decreases expression	2
Etoposide	increases expression	2
Valproic Acid	affects expression, decreases methylation, increases expression	2
Cyclosporine	decreases expression	2
ethylbenzene	affects cotreatment, decreases expression, increases methylation	1
methyleugenol	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
tobacco tar	decreases expression	1
periodate-oxidized adenosine	affects expression	1
methacrylaldehyde	affects cotreatment, decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	increases expression, affects cotreatment	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	affects response to substance	1
Acrolein	affects cotreatment, decreases expression	1
Cacodylic Acid	increases expression	1
Camptothecin	increases expression	1
Carbamazepine	affects expression	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4013170	Binding	Inhibition of recombinant human His-tagged GAB (P56 to V602 residues) expressed in Escherichia coli C41(DE3)pLysS using glutamine as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins by glutamate dehyd	Design, Synthesis, and Evaluation of Thiazolidine-2,4-dione Derivatives as a Novel Class of Glutaminase Inhibitors. — J Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.