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76  structures 2591  species 1  interaction 5126  sequences 27  architectures

Family: G_glu_transpept (PF01019)

Summary: Gamma-glutamyltranspeptidase

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Gamma-glutamyl transpeptidase Edit Wikipedia article

Gamma-glutamyltranspeptidase
Identifiers
Symbol G_glu_transpept
Pfam PF01019
InterPro IPR000101
PROSITE PDOC00404
gamma-glutamyltransferase
Identifiers
EC number 2.3.2.2
CAS number 9046-27-9
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
gamma-glutamyltransferase 1
Identifiers
Symbol GGT1
Alt. symbols GGT
Entrez 2678
HUGO 4250
OMIM 231950
RefSeq NM_001032364
UniProt P19440
Other data
Locus Chr. 22 q11.1-11.2
gamma-glutamyltransferase 2
Identifiers
Symbol GGT2
Alt. symbols GGT
Entrez 2679
HUGO 4251
OMIM 137181
RefSeq NM_002058
UniProt P36268
Other data
Locus Chr. 22 q11.1-11.2

Gamma-glutamyltransferase or gamma-glutamyl transpeptidase (also γ-glutamyltransferase, GGT, GGTP, gamma-GT) (EC 2.3.2.2) is an enzyme that transfers gamma-glutamyl functional groups. It is found in many tissues, the most notable one being the liver, and has significance in medicine as a diagnostic marker.

GGT[1] catalyzes the transfer of the gamma-glutamyl moiety of glutathione to an acceptor that may be an amino acid, a peptide or water (forming glutamate). GGT plays a key role in the gamma-glutamyl cycle, a pathway for the synthesis and degradation of glutathione and drug and xenobiotic detoxification.[2] Other lines of evidence indicate that GGT can also exert a prooxidant role, with regulatory effects at various levels in cellular signal transduction and cellular pathophysiology,[3]

Function

GGT is present in the cell membranes of many tissues, including the kidneys, bile duct, pancreas, gallbladder, spleen, heart, brain, and seminal vesicles.[4] It is involved in the transfer of amino acids across the cellular membrane[5] and leukotriene metabolism.[6] It is also involved in glutathione metabolism by transferring the glutamyl moiety to a variety of acceptor molecules including water, certain L-amino acids, and peptides, leaving the cysteine product to preserve intracellular homeostasis of oxidative stress.[7][8] This general reaction is:

(5-L-glutamyl)-peptide + an amino acid \rightleftharpoons peptide + 5-L-glutamyl amino acid

Structural studies

In prokaryotes and eukaryotes, it is an enzyme that consists of two polypeptide chains, a heavy and a light subunit, processed from a single chain precursor by an autocatalytic cleavage. The active site of GGT is known to be located in the light subunit.

Medical applications

GGT is predominantly used as a diagnostic marker for liver disease in medicine.

Blood test results for GGT suggest that the normal value for men is 15-85 IU/L, whereas for women it is 5-55 IU/L.[9]

Elevated serum GGT activity can be found in diseases of the liver, biliary system, and pancreas. In this respect, it is similar to alkaline phosphatase (ALP) in detecting disease of the biliary tract. Indeed, the two markers correlate well, though there is conflicting data about whether GGT has better sensitivity.[10][11] In general, ALP is still the first test for biliary disease. The main value of GGT over ALP is in verifying that ALP elevations are, in fact, due to biliary disease; ALP can also be increased in certain bone diseases, but GGT is not.[11] More recently, slightly elevated serum GGT has also been found to correlate with cardiovascular diseases and is under active investigation as a cardiovascular risk marker. GGT in fact accumulates in atherosclerotic plaques,[12] suggesting a potential role in pathogenesis of cardiovascular diseases,[13] and circulates in blood in the form of distinct protein aggregates,[14] some of which appear to be related to specific pathologies such as metabolic syndrome, alcohol addiction and chronic liver disease. High body mass index is associated with type 2 diabetes only in persons with high serum GGT.[15]

GGT is elevated by large quantities of alcohol ingestion. Determination of total serum GGT activity is however not specific to alcohol intoxication,[16] and the measurement of selected serum forms of the enzyme offer more specific information.[14] Isolated elevation or disproportionate elevation compared to other liver enzymes (such as ALP or ALT) may indicate alcohol abuse or alcoholic liver disease.[17] It may indicate excess alcohol consumption up to 3 or 4 weeks prior to the test. The mechanism for this elevation is unclear. Alcohol may increase GGT production by inducing hepatic microsomal production, or it may cause the leakage of GGT from hepatocytes.[18]

Numerous drugs can raise GGT levels, including barbiturates and phenytoin.[19] GGT elevation has also been occasionally reported following NSAIDs, St. John's wort, and aspirin. Elevated levels of GGT may also be due to congestive heart failure.[20]

Human proteins

GGT1; GGT2; GGT6; GGTL3; GGTL4; GGTLA1; GGTLA4;

References

  1. ^ Tate SS, Meister A (1985). "gamma-Glutamyl transpeptidase from kidney". Meth. Enzymol. Methods in Enzymology 113: 400–419. doi:10.1016/S0076-6879(85)13053-3. ISBN 978-0-12-182013-8. PMID 2868390. 
  2. ^ Siest G, Courtay C, Oster T, Michelet F, Visvikis A, Diederich M, Wellman M (1992). "Gamma-glutamyltransferase: nucleotide sequence of the human pancreatic cDNA. Evidence for a ubiquitous gamma-glutamyltransferase polypeptide in human tissues". Biochem. Pharmacol. 43 (12): 2527–2533. doi:10.1016/0006-2952(92)90140-E. PMID 1378736. 
  3. ^ Dominici S, Paolicchi A, Corti A, Maellaro E, Pompella A (2005). "Prooxidant reactions promoted by soluble and cell-bound γ-glutamyltransferase activity". Meth. Enzymol. 401: 483–500. doi:10.1016/S0076-6879(05)01029-3. PMID 16399404. 
  4. ^ Goldberg, DM (1980). "Structural, functional, and clinical aspects of gamma-glutamyltransferase". Crit Rev Clin Lab Sci 12 (1): 1–58. doi:10.3109/10408368009108725. PMID 6104563. 
  5. ^ Meister A (August 1974). "The gamma-glutamyl cycle. Diseases associated with specific enzyme deficiencies". Ann. Intern. Med. 81 (2): 247–53. PMID 4152527. 
  6. ^ Raulf M, Stüning M, König W (May 1985). "Metabolism of leukotrienes by L-gamma-glutamyl-transpeptidase and dipeptidase from human polymorphonuclear granulocytes". Immunology 55 (1): 135–47. PMC 1453575. PMID 2860060. 
  7. ^ Schulman JD, Goodman SI, Mace JW, Patrick AD, Tietze F, Butler EJ (July 1975). "Glutathionuria: inborn error of metabolism due to tissue deficiency of gamma-glutamyl transpeptidase". Biochem. Biophys. Res. Commun. 65 (1): 68–74. doi:10.1016/S0006-291X(75)80062-3. PMID 238530. 
  8. ^ Yokoyama H (June 2007). "[Gamma glutamyl transpeptidase (gammaGTP) in the era of metabolic syndrome]". Nihon Arukoru Yakubutsu Igakkai Zasshi (in Japanese) 42 (3): 110–24. PMID 17665541. 
  9. ^ General Laboratory Manual. Department of Pathology, Hackensack University Medical Centre. 2010. p. 117. Retrieved 20 November 2011. 
  10. ^ Betro MG, Oon RC, Edwards JB (November 1973). "Gamma-glutamyl transpeptidase in diseases of the liver and bone". Am. J. Clin. Pathol. 60 (5): 672–8. PMID 4148049. 
  11. ^ a b Lum G, Gambino SR (April 1972). "Serum gamma-glutamyl transpeptidase activity as an indicator of disease of liver, pancreas, or bone". Clin. Chem. 18 (4): 358–62. PMID 5012259. 
  12. ^ Emdin M, Pompella A, Paolicchi A (2005). "Editorial - Gamma-glutamyltransferase, atherosclerosis, and cardiovascular disease: triggering oxidative stress within the plaque". Circulation 112 (14): 2078–80. doi:10.1161/CIRCULATIONAHA.105.571919. PMID 16203922. 
  13. ^ Pompella A, Emdin M, Passino C, Paolicchi A (2004). "The significance of serum gamma-glutamyltransferase in cardiovascular diseases". Clin. Chem. Lab. Med. 42 (10): 1085–91. doi:10.1515/CCLM.2004.224. PMID 15552264. 
  14. ^ a b Franzini M, Bramanti E, Ottaviano V, Ghiri E, Scatena F, Pompella A, Donato L, Emdin M, Paolicchi A (2006). "A high performance gel filtration chromatography method for gamma-glutamyltransferase fraction analysis". Anal. Biochem. 374: 1–8. doi:10.1016/j.ab.2007.10.025. PMID 18023410. 
  15. ^ Lim JS, Lee DH, Park JY, Jin SH, Jacobs DR Jr (2007). "A strong interaction between serum gamma-glutamyltransferase and obesity on the risk of prevalent type 2 diabetes: results from the Third National Health and Nutrition Examination Survey". CLINICAL CHEMISTRY 53 (6): 1092–1098. doi:10.1016/j.jacl.2011.05.004. PMID 17478563. 
  16. ^ Lamy J, Baglin MC, Ferrant JP, Weill J (1974). "Determination de la gamma-glutamyl transpeptidase senque des ethyliques a la suite du sevrage". Clin Chim Acta 56: 169. 
  17. ^ Kaplan MM, et al. (1985). "Biochemical basis for serum enzyme abnormalities in alcoholic liver disease". In Chang NC, Chan NM. Research Monograph No. 17 (in Early identification of alcohol abuse) (NIAAA). p. 186. 
  18. ^ Barouki R, Chobert MN, Finidori J, Aggerbeck M, Nalpas B, Hanoune J (1983). "Ethanol effects in a rat hepatoma cell line: induction of gamma-glutamyltransferase". Hepatology 3 (3): 323–9. doi:10.1002/hep.1840030308. PMID 6132864. 
  19. ^ Rosalki SB, Tarlow D, Rau D (August 1971). "Plasma gamma-glutamyl transpeptidase elevation in patients receiving enzyme-inducing drugs". Lancet 2 (7720): 376–7. doi:10.1016/S0140-6736(71)90093-6. PMID 4105075. 
  20. ^ Ruttmann E, Brant LJ, Concin H, Diem G, Rapp K, Ulmer H (October 2005). "Gamma-glutamyltransferase as a risk factor for cardiovascular disease mortality: an epidemiological investigation in a cohort of 163,944 Austrian adults". Circulation 112 (14): 2130–7. doi:10.1161/CIRCULATIONAHA.105.552547. PMID 16186419. 

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External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000101

Gamma-glutamyltranspeptidase (EC) (GGT) [PUBMED:2868390] catalyzes the transfer of the gamma-glutamyl moiety of glutathione to an acceptor that may be an amino acid, a peptide or water (forming glutamate). GGT plays a key role in the gamma-glutamyl cycle, a pathway for the synthesis and degradation of glutathione and drug and xenobiotic detoxification [PUBMED:1378736]. In prokaryotes and eukaryotes, it is an enzyme that consists of two polypeptide chains, a heavy and a light subunit, processed from a single chain precursor by an autocatalytic cleavage. The active site of GGT is known to be located in the light subunit. The sequences of mammalian and bacterial GGT show a number of regions of high similarity [PUBMED:2570061]. Pseudomonas cephalosporin acylases (EC) that convert 7-beta-(4-carboxybutanamido)-cephalosporanic acid (GL-7ACA) into 7-aminocephalosporanic acid (7ACA) and glutaric acid are evolutionary related to GGT and also show some GGT activity [PUBMED:1358202]. Like GGT, these GL-7ACA acylases, are also composed of two subunits.

As an autocatalytic peptidase GGT belongs to MEROPS peptidase family T3 (gamma-glutamyltransferase family, clan PB(T)). The active site residue for members of this family and family T1 is C-terminal to the autolytic cleavage site. The type example is gamma-glutamyltransferase 1 from Escherichia coli.

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan NTN (CL0052), which has the following description:

In the N-terminal nucleophile aminohydrolases (Ntn hydrolases) the N-terminal residue provides two catalytic groups, nucleophile and proton donor. These enzymes use the side chain of the amino-terminal residue, incorporated in a beta-sheet, as the nucleophile in the catalytic attack at the carbonyl carbon. The nucleophile is cysteine in GAT, serine in penicillin acylase, and threonine in the proteasome. All the enzymes share an unusual fold in which the nucleophile and other catalytic groups occupy equivalent sites. This fold provides both the capacity for nucleophilic attack and the possibility of autocatalytic processing [1].

The clan contains the following 14 members:

AAT Asparaginase_2 CBAH DUF1933 DUF3700 G_glu_transpept GATase_2 GATase_4 GATase_6 GATase_7 Penicil_amidase Peptidase_C69 Phospholip_B Proteasome

Alignments

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(4706)
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RP35
(1043)
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RP75
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  Seed
(52)
Full
(5126)
Representative proteomes NCBI
(4680)
Meta
(4706)
RP15
(561)
RP35
(1043)
RP55
(1459)
RP75
(1814)
Alignment:
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  Seed
(52)
Full
(5126)
Representative proteomes NCBI
(4680)
Meta
(4706)
RP15
(561)
RP35
(1043)
RP55
(1459)
RP75
(1814)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
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External links

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Curation and family details

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Curation View help on the curation process

Seed source: Pfam-B_878 (release 3.0)
Previous IDs: none
Type: Family
Author: Bateman A
Number in seed: 52
Number in full: 5126
Average length of the domain: 454.30 aa
Average identity of full alignment: 29 %
Average coverage of the sequence by the domain: 87.76 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 19.1 19.1
Trusted cut-off 19.3 19.3
Noise cut-off 18.9 19.0
Model length: 510
Family (HMM) version: 16
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Species distribution

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Interactions

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G_glu_transpept

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the G_glu_transpept domain has been found. There are 76 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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