GGT1

Summary

GGT1 (gamma-glutamyltransferase 1, HGNC:4250) is a protein-coding gene on chromosome 22q11.23, encoding Glutathione hydrolase 1 proenzyme (P19440). Cleaves the gamma-glutamyl bond of extracellular glutathione (gamma-Glu-Cys-Gly), glutathione conjugates (such as maresin conjugate (13R)-S-glutathionyl-(14S)-hydroxy-(4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoate, MCTR1) and other gamma-glutamyl compounds (such as leukotriene C4, LTC4….

The enzyme encoded by this gene is a type I gamma-glutamyltransferase that catalyzes the transfer of the glutamyl moiety of glutathione to a variety of amino acids and dipeptide acceptors. The enzyme is composed of a heavy chain and a light chain, which are derived from a single precursor protein. It is expressed in tissues involved in absorption and secretion and may contribute to the etiology of diabetes and other metabolic disorders. Multiple alternatively spliced variants have been identified. There are a number of related genes present on chromosomes 20 and 22, and putative pseudogenes for this gene on chromosomes 2, 13, and 22.

Source: NCBI Gene 2678 — RefSeq curated summary.

At a glance

• Gene–disease (curated): gamma-glutamyl transpeptidase deficiency (Moderate, GenCC)
• GWAS associations: 19
• Clinical variants (ClinVar): 225 total — 2 pathogenic
• Phenotypes (HPO): 23
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001288833

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4250
Approved symbol	GGT1
Name	gamma-glutamyltransferase 1
Location	22q11.23
Locus type	gene with protein product
Status	Approved
Aliases	D22S672, D22S732, CD224
Ensembl gene	ENSG00000100031
Ensembl biotype	protein_coding
OMIM	612346
Entrez	2678

Gene structure

Transcript identifiers

Ensembl transcripts: 152 — 147 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000400380, ENST00000400382, ENST00000401885, ENST00000403838, ENST00000404223, ENST00000404532, ENST00000404920, ENST00000411974, ENST00000412658, ENST00000412898, ENST00000419133, ENST00000425895, ENST00000428855, ENST00000430289, ENST00000432867, ENST00000438643, ENST00000445029, ENST00000447416, ENST00000451366, ENST00000452551, ENST00000455483, ENST00000456869, ENST00000466310, ENST00000474191, ENST00000487766, ENST00000490087, ENST00000875906, ENST00000875907, ENST00000875908, ENST00000875909, ENST00000875910, ENST00000875911, ENST00000875912, ENST00000875913, ENST00000875914, ENST00000875915, ENST00000875916, ENST00000875917, ENST00000875918, ENST00000875919, ENST00000875920, ENST00000875921, ENST00000875922, ENST00000875923, ENST00000875924, ENST00000875925, ENST00000875926, ENST00000875927, ENST00000875928, ENST00000875929, ENST00000875930, ENST00000875931, ENST00000875932, ENST00000875933, ENST00000875934, ENST00000875935, ENST00000875936, ENST00000875937, ENST00000875938, ENST00000875939, ENST00000875940, ENST00000875941, ENST00000875942, ENST00000875943, ENST00000875944, ENST00000875945, ENST00000875946, ENST00000875947, ENST00000875948, ENST00000875949, ENST00000875950, ENST00000875951, ENST00000875952, ENST00000875953, ENST00000875954, ENST00000875955, ENST00000875956, ENST00000875957, ENST00000875958, ENST00000875959, ENST00000875960, ENST00000875961, ENST00000875962, ENST00000875963, ENST00000875964, ENST00000875965, ENST00000875966, ENST00000875967, ENST00000875968, ENST00000875969, ENST00000875970, ENST00000875972, ENST00000875973, ENST00000875975, ENST00000875977, ENST00000875978, ENST00000875979, ENST00000875980, ENST00000875981, ENST00000875983, ENST00000875985, ENST00000875987, ENST00000875988, ENST00000875990, ENST00000875992, ENST00000875993, ENST00000875994, ENST00000875995, ENST00000920975, ENST00000920976, ENST00000920977, ENST00000920978, ENST00000920979, ENST00000920980, ENST00000920981, ENST00000920982, ENST00000920983, ENST00000920984, ENST00000920985, ENST00000920986, ENST00000920987, ENST00000920988, ENST00000920989, ENST00000920990, ENST00000920991, ENST00000920992, ENST00000920993, ENST00000920994, ENST00000920995, ENST00000920996, ENST00000920997, ENST00000920998, ENST00000920999, ENST00000950670, ENST00000950671, ENST00000950672, ENST00000950673, ENST00000950674, ENST00000950675, ENST00000950676, ENST00000950677, ENST00000950678, ENST00000950679, ENST00000950680, ENST00000950681, ENST00000950682, ENST00000950683, ENST00000950684, ENST00000950685, ENST00000950686, ENST00000950687, ENST00000950688

RefSeq mRNA: 3 — MANE Select: NM_001288833 NM_001288833, NM_013421, NM_013430

CCDS: CCDS42992

Canonical transcript exons

ENST00000400382 — 16 exons

Exon	Start	End
ENSE00001542664	24603193	24603527
ENSE00003480697	24628693	24628996
ENSE00003562911	24607954	24608023
ENSE00003842157	24623780	24623916
ENSE00003842207	24620328	24620520
ENSE00003842294	24620913	24621070
ENSE00003843175	24615041	24615127
ENSE00003843637	24627432	24627619
ENSE00003843976	24628081	24628193
ENSE00003845351	24610250	24610531
ENSE00003847263	24627852	24627979
ENSE00003847468	24609965	24610033
ENSE00003847604	24628275	24628388
ENSE00003849687	24614776	24614906
ENSE00003850742	24623107	24623256
ENSE00003850998	24611075	24611245

Expression profiles

Bgee: expression breadth ubiquitous, 184 present calls, max score 94.88.

FANTOM5 (CAGE): breadth broad, TPM avg 2.4931 / max 60.6360, expressed in 655 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191430	0.8947	253
191428	0.8257	359
191429	0.3704	182
191427	0.3277	170
191426	0.0645	16
191425	0.0101	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	94.88	gold quality
mucosa of transverse colon	UBERON:0004991	94.85	gold quality
gall bladder	UBERON:0002110	94.79	gold quality
right lung	UBERON:0002167	94.50	gold quality
metanephros cortex	UBERON:0010533	94.28	gold quality
body of pancreas	UBERON:0001150	91.69	gold quality
upper lobe of left lung	UBERON:0008952	91.64	gold quality
right lobe of thyroid gland	UBERON:0001119	91.38	gold quality
adult mammalian kidney	UBERON:0000082	90.20	gold quality
left lobe of thyroid gland	UBERON:0001120	89.81	gold quality
upper lobe of lung	UBERON:0008948	89.66	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.81	gold quality
thyroid gland	UBERON:0002046	88.45	gold quality
pancreas	UBERON:0001264	87.44	gold quality
small intestine	UBERON:0002108	87.39	gold quality
cortex of kidney	UBERON:0001225	86.59	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.71	gold quality
body of stomach	UBERON:0001161	85.57	gold quality
left testis	UBERON:0004533	84.40	gold quality
islet of Langerhans	UBERON:0000006	84.20	gold quality
granulocyte	CL:0000094	84.11	gold quality
right testis	UBERON:0004534	83.58	gold quality
kidney	UBERON:0002113	83.46	gold quality
kidney epithelium	UBERON:0004819	83.44	silver quality
transverse colon	UBERON:0001157	83.01	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.00	gold quality
bone marrow cell	CL:0002092	82.65	gold quality
liver	UBERON:0002107	82.57	gold quality
stomach	UBERON:0000945	82.53	gold quality
testis	UBERON:0000473	81.74	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	26.67
E-ANND-3	yes	7.39
E-MTAB-6075	no	496.57

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETV4, IRF6, TFAP2A

miRNA regulators (miRDB)

6 targeting GGT1, 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-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-6878-3P	99.24	64.23	920
HSA-MIR-3127-3P	98.94	67.34	1055
HSA-MIR-6756-3P	98.94	66.79	1104
HSA-MIR-4308	97.56	67.13	1385

Literature-anchored findings (GeneRIF, showing 40)

• explore the relationship between the alteration in gamma-glutamyl transpeptidase (GGT) mRNA expression and the development of hepatocellular carcinoma (HCC) (PMID:11940314)
• Gamma-glutamyl transpeptidase activity mediates NF-kappaB activation through lipid peroxidation in human leukemia U937 cells. (PMID:12030366)
• Malignant lung tumors (squamous cell carcinoma and adenocarcinoma) had significantly increased levels of this enzyme. (PMID:12447480)
• Glucose intolerance is associated with elevated serum aminotransferase independent of obesity. (PMID:12480555)
• Gamma-glutamyl transpeptidase gene expression in liver, liver disease, and liver neoplasms. (PMID:12532447)
• The gamma-glutamyl transpeptidase activity in both oligoasthenospermic and azoospermic subjects were significantly lower than in asthenospermic and oligospermic individuals (PMID:12835487)
• there is a complete deficiency of LTD(4) biosynthesis in patients with a genetic deficiency of GGT which represents a new inborn error of cysteinyl leukotriene synthesis (PMID:14754911)
• Metabolic syndrome seemed to be directly, not indirectly through fatty liver, associated with the raised GGT level in Japanese women. No significant association between the raised GGT level and the presence of fatty liver. (PMID:15052692)
• Membrane GGT activity-often expressed at high levels in human malignancies-can oxidize extracellular AA and promote its uptake efficiently. (PMID:15528049)
• After adjustment for race, sex, age, cigarette smoking, alcohol intake, and body mass index (BMI), serum concentration of GGT across all deciles was positively associated with serum concentrations of CRP. (PMID:15694941)
• Transfection of activated Ras in human colon carcinoma cell line expressing wild-type Ras resulted in increased GGT, while reduced enzyme level was found in another cell line with constitutive Ras after transfection with dominant-negative Ras mutant. (PMID:16386375)
• An increase in serum GGT predicts onset of metabolic syndrome, incident CVD, and death suggesting that GGT is a marker of metabolic and cardiovascular risk. (PMID:17095717)
• The biliary IL-6 and TNF-alpha levels were positively correlated with serum DBIL, TBA and gamma-GT levels in infantile hepatitis syndrome subjects. (PMID:17109502)
• The role of high gammaGT activity in HepG2 cells can be connected with production of reactive oxygen species and with S-thiolation with Cys and Cys-Gly that can influence activity of caspase 3. (PMID:17141888)
• In contrast to the E Coli GGT1, in the human enzyme, a specific residue in the Cys-Gly binding site played a critical role in recognizing the Cys-Gly moiety or the acceptor molecules by interacting with the C-terminal carboxy group (PMID:17260973)
• GGT1 is a biological tumor marker for epithelial ovarian cancers. (PMID:17503391)
• Modest elevation of GGT observed in overweight children may be of pathophysiological importance in the long term (PMID:17652002)
• Association between the serum level parameters of adiposity and lipid profile. (PMID:17698237)
• The results indicate that “silent” apoptosemia occurs in T1 and T2 diabetic children and suggest elevated GGT in diabetic children could be due to release from apoptotic cells (PMID:17895524)
• Serum GGT may be an additional marker of arterial stiffness, especially in men, though the relationship with arterial stiffness was very weak. (PMID:17965490)
• There was a positive association between serum GGT level and peripheral artery disease among men, particularly non-Hispanic white and nondrinker men, but not among women (PMID:18037420)
• Data revealed higher gamma-glutamyltranspeptidase for women with a family history of diabetes, when adjusted for age and BMI. (PMID:18242760)
• the presence of diabetes mellitus may attenuate the effects of GGT on blood pressure in hypertensive patients (PMID:18441507)
• gamma-glutamyltransferase may have a role in risk of cancer incidence in men (PMID:18483283)
• Alanine aminotransferase, alanine/aspartate aminotransferase ratio, and gamma-glutamyl transferase are associated with the MetS but not with angiographically determined coronary atherosclerosis. (PMID:18708042)
• gamma-glutamyltransferase is not associated with peripheral arterial disease in type 2 diabetic patients (PMID:18715564)
• These results suggest that higher serum GGT levels are associated with prehypertension or hypertension in the general male population. (PMID:18987455)
• High gamma-glutamyltransferase in end-stage renal disease patients is a strong, independent risk marker for all cause and cardiovascular death. (PMID:19034330)
• As serum gamma-glutamyltransferase concentration increased, the association of body mass index with atherogenic dyslipidemia and glycemic control strengthened. (PMID:19057528)
• Central obesity and metabolic syndrome were associated with elevated levels of gamma-glutamyltransferase. (PMID:19148121)
• Serum gamma-glutamyl transferase may have a role in mortality in persons undergoing coronary angiography (PMID:19695568)
• Data show that the b-GGT present in human plasma can be produced by tissues other than the liver, thus explaining the increase of serum GGT observed in diseases of other organs. (PMID:19863187)
• there was no association between increasing levels of serum GGT and chronic kidney disease in a sample of US adults (PMID:20090360)
• Gamma-glutamyltransferase has a role in coronary heart disease (PMID:20092819)
• Plasma bilirubin and gamma-glutamyltransferase activity are inversely related in dyslipidemic patients with metabolic syndrome (PMID:20129611)
• The association of coffee and green tea consumption with serum activities of liver enzymes in free-living Japanese men and women was examined, focusing on sex difference and effect modifications of alcohol and obesity. (PMID:20205615)
• gamma-glutamyltransferase may have a role in incidence of type 2 diabetes in Japan (PMID:20404051)
• PCSK9 has a role in regulating GGT level in diabetic patients, suggesting potential interaction between PCSK9 and liver function (PMID:20452593)
• Lead SNP rs4820599 is in high linkage disequilibrium (LD; pairwise r(2): 0.69) and tagSNP rs2017869 is in strong LD (pairwise r(2): 0.96) with SNP rs5751901, which has been reported to be associated with increased GGT1 serum levels in pancreatic cancer. (PMID:20484958)
• Serum GGT levels were higher in acute coronary syndrome patients but there was no difference between diabetic and non-diabetic subgroups. (PMID:20625912)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	ggt1b	ENSDARG00000018342
danio_rerio	ggt1a	ENSDARG00000023526
danio_rerio	ggt1l2.1	ENSDARG00000075055
danio_rerio	si:ch73-236c18.3	ENSDARG00000075541
danio_rerio	ggt1l2.2	ENSDARG00000087054
danio_rerio	si:ch73-59p9.2	ENSDARG00000091254
danio_rerio	si:dkey-222h21.12	ENSDARG00000092350
danio_rerio		ENSDARG00000098576
mus_musculus	Ggt1	ENSMUSG00000006345
rattus_norvegicus	Ggt1	ENSRNOG00000047697
drosophila_melanogaster	CG17636	FBGN0025837
drosophila_melanogaster	Ggt-1	FBGN0030932

Paralogs (6): GGT5 (ENSG00000099998), GGTLC2 (ENSG00000100121), GGT7 (ENSG00000131067), GGTLC1 (ENSG00000149435), GGT6 (ENSG00000167741), GGTLC3 (ENSG00000274252)

Protein

Protein identifiers

Glutathione hydrolase 1 proenzyme — P19440 (reviewed: P19440)

Alternative names: Gamma-glutamyltransferase 1, Gamma-glutamyltranspeptidase 1, Leukotriene-C4 hydrolase

All UniProt accessions (17): P19440, A0A140VJJ9, B5MC34, B5MC36, C9JGF3, C9JIY6, E7EM62, E7ENJ5, E7ERN9, E7ESL5, E7ET76, E7ETJ6, E7ETN1, E7ETR7, E7ETU4, E7EVF8, E9PHP2

UniProt curated annotations — full annotation on UniProt →

Function. Cleaves the gamma-glutamyl bond of extracellular glutathione (gamma-Glu-Cys-Gly), glutathione conjugates (such as maresin conjugate (13R)-S-glutathionyl-(14S)-hydroxy-(4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoate, MCTR1) and other gamma-glutamyl compounds (such as leukotriene C4, LTC4). The metabolism of glutathione by GGT1 releases free glutamate and the dipeptide cysteinyl-glycine, which is hydrolyzed to cysteine and glycine by dipeptidases. In the presence of high concentrations of dipeptides and some amino acids, can also catalyze a transpeptidation reaction, transferring the gamma-glutamyl moiety to an acceptor amino acid to form a new gamma-glutamyl compound. Contributes to cysteine homeostasis, glutathione homeostasis and in the conversion of the leukotriene LTC4 to LTD4. Seems to be catalytically inactive.

Subunit / interactions. Heterodimer composed of the light and heavy chains. The active site is located in the light chain.

Subcellular location. Cell membrane.

Tissue specificity. Detected in fetal and adult kidney and liver, adult pancreas, stomach, intestine, placenta and lung. There are several other tissue-specific forms that arise from alternative promoter usage but that produce the same protein. Lung-specific.

Post-translational modifications. N-glycosylated on both chains. Contains hexoses, hexosamines and sialic acid residues. Glycosylation profiles tested in kidney and liver tissues reveal the presence of tissue-specific and site-specific glycan composition, despite the overlap in composition among the N-glycans. A total of 36 glycan compositions, with 40 unique structures are observed. Up to 15 different glycans are observed at a single site, with site-specific variation in glycan composition. The difference in glycosylation profiles in the 2 tissues do not affect the enzyme activity. Cleaved by autocatalysis into a large and a small subunit and the autocatalytic cleavage is essential to the functional activation of the enzyme.

Disease relevance. Glutathionuria (GLUTH) [MIM:231950] A very rare, autosomal recessive metabolic disorder characterized by the presence of glutathione in the urine, due to generalized gamma-glutamyl transpeptidase deficiency. Most patients manifest mild to moderate intellectual disability, and behavioral disturbance. Seizures, tremor, marfanoid features and strabismus are observed in some patients. The disease is caused by variants affecting the gene represented in this entry. A large homozygous deletion that removes several exons of all isoforms of GGT1 has been found in one family affected by glutathionuria.

Activity regulation. Activated by autocatalytic cleavage. Inhibited by serine-borate.

Pathway. Lipid metabolism; leukotriene D4 biosynthesis. Sulfur metabolism; glutathione metabolism.

Miscellaneous. Cys-454 was thought to bind the gamma-glutamyl moiety, but mutagenesis of this residue had no effect on activity. Chloride ions bound in the active site cavity may contribute to stabilize the protein fold. Produced by alternative promoter usage. Produced by alternative splicing of isoform 1. Produced by alternative promoter usage.

Similarity. Belongs to the gamma-glutamyltransferase family.

Isoforms (3)

UniProt ID	Names	Canonical?
P19440-1	1	yes
P19440-2	2
P19440-3	3

RefSeq proteins (3): NP_001275762, NP_038265, NP_038347 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000101	GGT_peptidase	Family
IPR029055	Ntn_hydrolases_N	Homologous_superfamily
IPR043137	GGT_ssub_C	Homologous_superfamily
IPR043138	GGT_lsub	Homologous_superfamily
IPR055262	GGT_CS	Conserved_site

Pfam: PF01019

Catalyzed reactions (Rhea), 5 shown:

• an N-terminal (5-L-glutamyl)-[peptide] + an alpha-amino acid = 5-L-glutamyl amino acid + an N-terminal L-alpha-aminoacyl-[peptide] (RHEA:23904)
• glutathione + H2O = L-cysteinylglycine + L-glutamate (RHEA:28807)
• leukotriene C4 + H2O = leukotriene D4 + L-glutamate (RHEA:31563)
• (13R)-S-glutathionyl-(14S)-hydroxy-(4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoate + H2O = (13R)-S-cysteinylglycyl-(14S)-hydroxy-(4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoate + L-glutamate (RHEA:53512)
• an S-substituted glutathione + H2O = an S-substituted L-cysteinylglycine + L-glutamate (RHEA:59468)

UniProt features (107 total): helix 24, mutagenesis site 22, strand 20, glycosylation site 7, turn 6, sequence variant 6, sequence conflict 6, binding site 5, splice variant 3, chain 2, disulfide bond 2, topological domain 2, transmembrane region 1, active site 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
7LD9	X-RAY DIFFRACTION	1.42
4GDX	X-RAY DIFFRACTION	1.67
6XPB	X-RAY DIFFRACTION	1.74
7LA5	X-RAY DIFFRACTION	2.07
4ZC6	X-RAY DIFFRACTION	2.1
4ZBK	X-RAY DIFFRACTION	2.18
5V4Q	X-RAY DIFFRACTION	2.2
4GG2	X-RAY DIFFRACTION	2.21
4ZCG	X-RAY DIFFRACTION	2.22
6XPC	X-RAY DIFFRACTION	2.26
7LBC	X-RAY DIFFRACTION	2.28
4Z9O	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P19440-F1	94.84	0.89

Functional residue map

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

Catalytic / active sites (1): 381 (nucleophile)

Ligand- & substrate-binding residues (5): 474; 107; 399–401; 423; 451–452

Disulfide bonds (2): 50–74, 192–196

Glycosylation sites (7): 95, 120, 230, 266, 297, 344, 511

Mutagenesis-validated functional residues (22):

Position	Phenotype
100	no effect on gamma-glutamyltranspeptidase activity.
102	no effect on gamma-glutamyltranspeptidase activity.
107	reduces enzyme gamma-glutamyltranspeptidase activity by 99%.
107	abolishes gamma-glutamyltranspeptidase activity.
108	reduces gamma-glutamyltranspeptidase activity by 98%.
112	no effect on gamma-glutamyltranspeptidase activity.
139	no effect on gamma-glutamyltranspeptidase activity.
147	no effect on gamma-glutamyltranspeptidase activity.
150	no effect on gamma-glutamyltranspeptidase activity.
192	loss of autocatalytic cleavage, cell membrane localization and decrease in gamma-glutamyltranspeptidase activity; when a
193	loss of autocatalytic cleavage, cell membrane localization and decrease in gamma-glutamyltranspeptidase activity; when a
383	reduces gamma-glutamyltranspeptidase activity by 66%.
385	no effect on gamma-glutamyltranspeptidase activity.
413	no effect on gamma-glutamyltranspeptidase activity.
422	reduces enzyme gamma-glutamyltranspeptidase activity by 90%.
423	abolishes gamma-glutamyltranspeptidase activity. increases km for d-gamma-glutamyl-p-nitroanalide by over 1000-fold.
425	no effect on gamma-glutamyltranspeptidase activity.
451	reduces gamma-glutamyltranspeptidase activity by 99%. abolishes activity; when associated with a-452.
452	reduces gamma-glutamyltranspeptidase activity by 99%. abolishes activity; when associated with a-451.
454	no effect on gamma-glutamyltranspeptidase activity.
505	reduces gamma-glutamyltranspeptidase activity by 90%.
545	reduces enzyme activity by 97%.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-174403	Glutathione synthesis and recycling
R-HSA-2142691	Synthesis of Leukotrienes (LT) and Eoxins (EX)
R-HSA-5423646	Aflatoxin activation and detoxification
R-HSA-5579022	Defective GGT1 causes GLUTH
R-HSA-9035968	Defective GGT1 in aflatoxin detoxification causes GLUTH
R-HSA-9664535	LTC4-CYSLTR mediated IL4 production
R-HSA-9753281	Paracetamol ADME

MSigDB gene sets: 288 (showing top): REACTOME_BIOLOGICAL_OXIDATIONS, GOBP_INFLAMMATORY_RESPONSE, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, GOBP_GLUTAMATE_METABOLIC_PROCESS, GOBP_MODIFIED_AMINO_ACID_CATABOLIC_PROCESS, GOBP_SERINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, GOBP_MALE_GAMETE_GENERATION, GOBP_LEUKOTRIENE_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS

GO Biological Process (16): regulation of immune system process (GO:0002682), proteolysis (GO:0006508), amino acid metabolic process (GO:0006520), glutamate metabolic process (GO:0006536), fatty acid metabolic process (GO:0006631), leukotriene metabolic process (GO:0006691), glutathione biosynthetic process (GO:0006750), glutathione catabolic process (GO:0006751), spermatogenesis (GO:0007283), L-cysteine biosynthetic process (GO:0019344), peptide modification (GO:0031179), zymogen activation (GO:0031638), regulation of inflammatory response (GO:0050727), leukotriene D4 biosynthetic process (GO:1901750), lipid metabolic process (GO:0006629), glutathione metabolic process (GO:0006749)

GO Molecular Function (9): peptidyltransferase activity (GO:0000048), leukotriene-C(4) hydrolase activity (GO:0002951), glutathione gamma-glutamate hydrolase (GO:0036374), obsolete leukotriene C4 gamma-glutamyl transferase activity (GO:0103068), protein binding (GO:0005515), peptidase activity (GO:0008233), transferase activity (GO:0016740), acyltransferase activity (GO:0016746), hydrolase activity (GO:0016787)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Metabolic disorders of biological oxidation enzymes	2
Glutathione conjugation	1
Arachidonate metabolism	1
Biological oxidations	1
Anti-inflammatory response favouring Leishmania parasite infection	1
Drug ADME	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
primary metabolic process	2
glutathione metabolic process	2
sulfur compound biosynthetic process	2
catalytic activity, acting on a protein	2
omega peptidase activity	2
catalytic activity	2
immune system process	1
regulation of biological process	1
protein metabolic process	1
amino acid metabolic process	1
dicarboxylic acid metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
icosanoid metabolic process	1
nonribosomal peptide biosynthetic process	1
modified amino acid biosynthetic process	1
modified amino acid catabolic process	1
sulfur compound catabolic process	1
developmental process involved in reproduction	1
male gamete generation	1
sulfur amino acid biosynthetic process	1
serine family amino acid biosynthetic process	1
L-amino acid biosynthetic process	1
proteinogenic amino acid biosynthetic process	1
peptide metabolic process	1
protein processing	1
inflammatory response	1
regulation of defense response	1
regulation of response to external stimulus	1
leukotriene biosynthetic process	1
fatty acid derivative biosynthetic process	1
modified amino acid metabolic process	1
sulfur compound metabolic process	1
aminoacyltransferase activity	1
catalytic activity, acting on a tRNA	1
threonine-type peptidase activity	1
binding	1
hydrolase activity	1
transferase activity	1
membrane	1

Protein interactions and networks

STRING

1050 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GGT1	AGA	P20933	745
GGT1	TALDO1	P37837	732
GGT1	ABCB4	P21439	683
GGT1	DDC	P20711	681
GGT1	ZBTB20	Q9HC78	666
GGT1	GGCT	O75223	661
GGT1	ZHX2	Q9Y6X8	652
GGT1	ALPG	P10696	633
GGT1	GPT	P24298	626
GGT1	GOT1L1	Q8NHS2	624
GGT1	GOT1	P17174	621
GGT1	ABCB11	O95342	611
GGT1	RABGGTB	P53611	591
GGT1	GLYAT	Q6IB77	585
GGT1	CRYGD	P07320	575

IntAct

12 interactions, top by confidence:

A	B	Type	Score
GGT1	GGT2P	psi-mi:“MI:0915”(physical association)	0.500
GGT1	NAMPT	psi-mi:“MI:0915”(physical association)	0.370
CD81	STX3	psi-mi:“MI:0914”(association)	0.350
CD81	PVR	psi-mi:“MI:0914”(association)	0.350
CD81	CD276	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	TNFRSF10A	psi-mi:“MI:0914”(association)	0.350
GGT1	POTEF	psi-mi:“MI:0914”(association)	0.350
ECSIT	NDUFA2	psi-mi:“MI:0914”(association)	0.350
GGT1		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (36): GGT2 (Affinity Capture-MS), GGT1 (Co-fractionation), GGT1 (Affinity Capture-Western), GGT2 (Affinity Capture-MS), GGT1 (Proximity Label-MS), GGT1 (Affinity Capture-MS), GGT1 (Affinity Capture-MS), GGT1 (Proximity Label-MS), GGT2 (Affinity Capture-MS), PDXDC2P (Affinity Capture-MS), NCDN (Affinity Capture-MS), TAB1 (Affinity Capture-MS), SLC25A31 (Affinity Capture-MS), GGT1 (Affinity Capture-MS), POTEF (Affinity Capture-MS)

ESM2 similar proteins: A6NGU5, B5MD39, B6EWW8, D4B387, F8S0Z7, O35409, O77564, P07314, P07686, P0DPU3, P0DPU6, P15693, P17439, P19111, P19440, P20735, P21588, P24822, P24823, P36268, P36269, P49614, P58242, P70627, Q04609, Q05927, Q0V8L2, Q14390, Q29548, Q2KHZ8, Q501L1, Q5RFI5, Q5RFU0, Q5TYS5, Q5XIG6, Q60928, Q680I5, Q68FH4, Q6DH69, Q6GMR7

Diamond homologs: A6NGU5, B5MD39, B8NM71, D4B387, O14194, P07314, P0DPU3, P0DPU6, P18956, P19440, P20735, P36267, P36268, P36269, P54422, P63186, Q05902, Q0V8L2, Q14390, Q60928, Q680I5, Q8VYW6, Q99JP7, Q99MZ4, Q9BX51, Q9CAR5, Q9I406, Q9M0G0, Q9QWE9, Q9UJ14, Q9US04, Q9Z2A9, A6T9C8, P15557, Q05053, Q51693, Q6P531, Q6IE08, O05218, A7YWM1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	145
Likely benign	28
Benign	33

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
253500	GRCh37/hg19 22q11.23(chr22:24401196-25010751)x3	Pathogenic
545540	NC_000022.10:g.24992587_25009579delinsGCCTGTAATCCCA	Pathogenic

SpliceAI

2832 predictions. Top by Δscore:

Variant	Effect	Δscore
22:24611066:T:TA	acceptor_gain	1.0000
22:24611067:G:A	acceptor_gain	1.0000
22:24611073:A:AG	acceptor_gain	1.0000
22:24611074:G:GG	acceptor_gain	1.0000
22:24611074:GCA:G	acceptor_gain	1.0000
22:24611074:GCAGA:G	acceptor_gain	1.0000
22:24611243:G:GT	donor_gain	1.0000
22:24611243:GAGG:G	donor_loss	1.0000
22:24611246:GTGA:G	donor_loss	1.0000
22:24611247:T:G	donor_loss	1.0000
22:24614767:ACAT:A	acceptor_gain	1.0000
22:24614769:A:AG	acceptor_gain	1.0000
22:24614769:AT:A	acceptor_gain	1.0000
22:24614769:ATG:A	acceptor_gain	1.0000
22:24614770:T:G	acceptor_gain	1.0000
22:24614770:T:TA	acceptor_gain	1.0000
22:24614770:TGGCA:T	acceptor_loss	1.0000
22:24614771:G:A	acceptor_gain	1.0000
22:24614771:GGCAG:G	acceptor_loss	1.0000
22:24614772:GCAG:G	acceptor_loss	1.0000
22:24614773:CAGG:C	acceptor_loss	1.0000
22:24614774:A:AG	acceptor_gain	1.0000
22:24614774:A:G	acceptor_loss	1.0000
22:24614774:AG:A	acceptor_gain	1.0000
22:24614774:AGG:A	acceptor_gain	1.0000
22:24614775:G:A	acceptor_loss	1.0000
22:24614775:G:GG	acceptor_gain	1.0000
22:24614775:GG:G	acceptor_gain	1.0000
22:24614775:GGG:G	acceptor_gain	1.0000
22:24614775:GGGA:G	acceptor_gain	1.0000

AlphaMissense

3684 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:24627603:A:C	S398R	0.995
22:24627605:C:A	S398R	0.995
22:24627605:C:G	S398R	0.995
22:24627913:T:C	F424L	0.995
22:24627915:C:A	F424L	0.995
22:24627915:C:G	F424L	0.995
22:24623840:G:C	R315P	0.994
22:24627897:T:A	N418K	0.994
22:24627897:T:G	N418K	0.994
22:24628811:G:T	R561M	0.994
22:24623858:G:C	R321P	0.993
22:24623851:G:C	A319P	0.992
22:24627940:T:C	F433L	0.991
22:24627942:T:A	F433L	0.991
22:24627942:T:G	F433L	0.991
22:24628812:G:C	R561S	0.991
22:24628812:G:T	R561S	0.991
22:24627912:C:A	D423E	0.990
22:24627912:C:G	D423E	0.990
22:24628811:G:C	R561T	0.990
22:24627614:C:A	N401K	0.989
22:24627614:C:G	N401K	0.989
22:24627896:A:T	N418I	0.989
22:24627916:A:C	S425R	0.989
22:24627918:C:A	S425R	0.989
22:24627918:C:G	S425R	0.989
22:24628804:G:C	D559H	0.989
22:24615065:G:C	R107P	0.988
22:24620404:G:C	W153C	0.988
22:24620404:G:T	W153C	0.988

dbSNP variants (sampled 300 via entrez): RS1000038222 (22:24610687 G>C), RS1000175745 (22:24610956 C>T), RS1000232388 (22:24588993 C>T), RS1000266797 (22:24589237 A>G), RS1000472834 (22:24616515 T>C), RS1000491186 (22:24598646 C>T), RS1000616149 (22:24587452 C>T), RS1000643265 (22:24593127 A>G), RS1000647590 (22:24603841 G>A), RS1000826893 (22:24621648 T>A), RS1000829431 (22:24595227 G>T), RS1000963711 (22:24622115 T>A,C), RS1001009331 (22:24585860 T>C), RS1001045961 (22:24609019 G>A), RS1001137353 (22:24627273 T>C)

Disease associations

OMIM: gene MIM:612346 | disease phenotypes: MIM:231950

GenCC curated gene-disease

Disease	Classification	Inheritance
gamma-glutamyl transpeptidase deficiency	Moderate	Autosomal dominant

Mondo (1): gamma-glutamyl transpeptidase deficiency (MONDO:0009285)

Orphanet (1): Gamma-glutamyl transpeptidase deficiency (Orphanet:33573)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000486	Strabismus
HP:0000601	Hypotelorism
HP:0000964	Eczematoid dermatitis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0002019	Constipation
HP:0002075	Dysdiadochokinesis
HP:0002099	Asthma
HP:0002282	Gray matter heterotopia
HP:0002345	Action tremor
HP:0003593	Infantile onset
HP:0011968	Feeding difficulties
HP:0034445	Reduced gamma-glutamyltransferase level
HP:0034456	Elevated circulating glutathione concentration
HP:0034586	Glutathionuria
HP:6000578	Reduced tissue gamma-glutamyltransferase activity

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST000189_29	Protein quantitative trait loci	2.000000e-07
GCST000248_7	Liver enzyme levels	4.000000e-11
GCST000583_23	Hematological and biochemical traits	8.000000e-20
GCST001234_7	Gamma glutamyl transpeptidase	7.000000e-53
GCST001277_20	Liver enzyme levels (gamma-glutamyl transferase)	1.000000e-109
GCST002481_6	Acne (severe)	6.000000e-07
GCST006019_10	Gamma glutamyl transferase levels	4.000000e-300
GCST006249_34	Serum metabolite levels	3.000000e-12
GCST009159_14	Blood protein levels	2.000000e-08
GCST009733_1	Urinary metabolite levels in chronic kidney disease	3.000000e-16
GCST009733_2	Urinary metabolite levels in chronic kidney disease	2.000000e-12
GCST009733_3	Urinary metabolite levels in chronic kidney disease	5.000000e-12
GCST009733_4	Urinary metabolite levels in chronic kidney disease	3.000000e-15
GCST009733_5	Urinary metabolite levels in chronic kidney disease	3.000000e-14
GCST009735_21	Urinary metabolite modules (eigenmetabolites) in chronic kidney disease	2.000000e-11
GCST010045_1	Gamma glutamyl transferase levels	5.000000e-11
GCST011349_31	Gamma glutamyl transferase levels	0.000000e+00
GCST012020_513	Serum metabolite levels	9.000000e-37
GCST90013407_7	Liver enzyme levels (gamma-glutamyl transferase)	2.000000e-308

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0004747	protein measurement
EFO:0005116	urinary metabolite measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536836	Glutathionuria (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5696 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 694,636 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL25	ASPIRIN	4	694,602
CHEMBL3039733	CROBENETINE	2	34

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2017869	GGT1		0.00	0
rs5751901	GGT1		0.00	0

ChEMBL bioactivities

15 potent at pChembl≥5 of 44 total, top 15 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.30	Ki	5	nM	CHEMBL87796
8.27	Ki	5.4	nM	CHEMBL5220943
7.60	Ki	25	nM	CHEMBL5220943
7.60	Ki	25	nM	CHEMBL87796
7.41	IC50	39	nM	CHEMBL5286162
7.35	Ki	45	nM	CHEMBL5219012
7.11	Ki	77	nM	CHEMBL5219012
6.49	IC50	322	nM	CROBENETINE
6.04	Ki	920	nM	CHEMBL5400857
5.62	IC50	2400	nM	CHEMBL3885040
5.55	Ki	2800	nM	CHEMBL5400857
5.51	IC50	3100	nM	CHEMBL3884872
5.48	IC50	3300	nM	CHEMBL1222043
5.11	IC50	7800	nM	CHEMBL3885443
5.00	IC50	9900	nM	CHEMBL3883795

PubChem BioAssay actives

15 with measured affinity, of 111 total; 11 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
(2S)-2-amino-4-boronobutanoic acid	2012182: Inhibition of GGT1 (unknown origin) transpeptidation assessed as inhibition constant using L-GpNA as substrate in presence of Gly-Gly	ki	0.0050	uM
(2S)-2-amino-4-boronobutanoic acid;hydrochloride	1917924: Inhibition of human GGT1 transpeptidation in Pichia pastoris using L-GpNA as substrate in presence of Gly-Gly	ki	0.0054	uM
(1S,9R)-10-[(2S)-2-methoxypropyl]-1,13,13-trimethyl-10-azatricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-6-ol	1960003: Inhibition of human GGT1	ic50	0.0390	uM
(2R)-2-amino-4-boronobutanoic acid;hydrochloride	1917924: Inhibition of human GGT1 transpeptidation in Pichia pastoris using L-GpNA as substrate in presence of Gly-Gly	ki	0.0450	uM
(1S,9R)-1,13,13-trimethyl-10-[(2S)-2-phenylmethoxypropyl]-10-azatricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-6-ol	1960003: Inhibition of human GGT1	ic50	0.3220	uM
2-amino-4-borono-2-methylbutanoic acid	2012182: Inhibition of GGT1 (unknown origin) transpeptidation assessed as inhibition constant using L-GpNA as substrate in presence of Gly-Gly	ki	0.9200	uM
N-[(2S)-1-amino-3-(4-fluorophenyl)-1-oxopropan-2-yl]-4-[1-(3,4-dichlorophenyl)-4-(2-methylsulfanylethyl)-3-pyridin-3-ylpyrazol-5-yl]oxybutanamide	1335609: Inhibition of recombinant GGT1 (unknown origin) using GGPP as substrate preincubated for 5 mins followed by protein addition measured over 20 mins by fluorescence assay	ic50	2.4000	uM
N-[(2S)-1-amino-3-(4-methoxyphenyl)-1-oxopropan-2-yl]-4-[1-(3,4-dichlorophenyl)-4-(2-methylsulfanylethyl)-3-pyridin-3-ylpyrazol-5-yl]oxybutanamide	1335609: Inhibition of recombinant GGT1 (unknown origin) using GGPP as substrate preincubated for 5 mins followed by protein addition measured over 20 mins by fluorescence assay	ic50	3.1000	uM
N-[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]-4-[1-(3,4-dichlorophenyl)-4-(2-methylsulfanylethyl)-3-pyridin-3-ylpyrazol-5-yl]oxybutanamide	1335609: Inhibition of recombinant GGT1 (unknown origin) using GGPP as substrate preincubated for 5 mins followed by protein addition measured over 20 mins by fluorescence assay	ic50	3.3000	uM
N-[(2S)-1-amino-1-oxo-3-pyridin-4-ylpropan-2-yl]-4-[1-(3,4-dichlorophenyl)-4-(2-methylsulfanylethyl)-3-pyridin-3-ylpyrazol-5-yl]oxybutanamide	1335609: Inhibition of recombinant GGT1 (unknown origin) using GGPP as substrate preincubated for 5 mins followed by protein addition measured over 20 mins by fluorescence assay	ic50	7.8000	uM
(2S)-N-[3-[1-(3,4-dichlorophenyl)-4-(2-methylsulfanylethyl)-3-pyridin-3-ylpyrazol-5-yl]oxypropyl]-2-(methanesulfonamido)-3-(4-methoxyphenyl)propanamide	1335609: Inhibition of recombinant GGT1 (unknown origin) using GGPP as substrate preincubated for 5 mins followed by protein addition measured over 20 mins by fluorescence assay	ic50	9.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression, affects cotreatment	3
entinostat	increases expression, affects cotreatment	2
(+)-JQ1 compound	decreases expression	2
Arsenic	decreases response to substance, affects cotreatment, decreases expression, increases abundance	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Tretinoin	increases expression	2
aristolochic acid I	decreases expression	1
OTX015	decreases expression	1
mivebresib	decreases expression	1
bismuth tripotassium dicitrate	decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression, increases expression	1
arsenite	increases abundance, increases expression	1
brequinar	decreases expression	1
nefazodone	affects cotreatment, increases expression	1
tamibarotene	increases expression	1
antimonite	increases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
abrine	increases expression	1
pyrachlostrobin	increases expression	1
darinaparsin	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
Atazanavir Sulfate	affects cotreatment, increases expression	1
Irinotecan	decreases expression	1
Decitabine	increases expression	1
Zoledronic Acid	decreases expression	1

ChEMBL screening assays

17 unique, capped per target: 17 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1014320	Binding	Inhibition of gamma-glutamyltranspeptidase by colorimetric assay	10H-Phenothiazines: a new class of enzyme inhibitors for inflammatory diseases. — Eur J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1WH	Abcam A-549 GGT1 KO	Cancer cell line	Male
CVCL_D2AW	Abcam HCT 116 GGT1 KO	Cancer cell line	Male
CVCL_D2NF	Abcam THP-1 GGT1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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