Gamma-glutamyltransferase

Gamma-glutamyltransferase (also γ-glutamyltransferase, GGT, gamma-GT, Gamma-Glutamyl Transpeptidase[1]; EC 2.3.2.2) is a transferase (a type of enzyme) that catalyzes the transfer of gamma-glutamyl functional groups from molecules such as glutathione to an acceptor that may be an amino acid, a peptide or water (forming glutamate).[1][2]:268 GGT plays a key role in the gamma-glutamyl cycle, a pathway for the synthesis and degradation of glutathione as well as drug and xenobiotic detoxification.[3] Other lines of evidence indicate that GGT can also exert a pro-oxidant role, with regulatory effects at various levels in cellular signal transduction and cellular pathophysiology.[4] This transferase is found in many tissues, the most notable one being the liver, and has significance in medicine as a diagnostic marker.

Gamma-glutamyl transpeptidase
Identifiers
SymbolG_glu_transpept
PfamPF01019
InterProIPR000101
PROSITEPDOC00404
Membranome274
gamma-glutamyltransferase
Identifiers
EC number2.3.2.2
CAS number9046-27-9
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
gamma-glutamyltransferase 1
Identifiers
SymbolGGT1
Alt. symbolsGGT
NCBI gene2678
HGNC4250
OMIM231950
RefSeqNM_001032364
UniProtP19440
Other data
EC number2.3.2.2
LocusChr. 22 q11.1-11.2
gamma-glutamyltransferase 2
Identifiers
SymbolGGT2
Alt. symbolsGGT
NCBI gene2679
HGNC4251
OMIM137181
RefSeqNM_002058
UniProtP36268
Other data
EC number2.3.2.2
LocusChr. 22 q11.1-11.2

Nomenclature

The name γ-glutamyltransferase is preferred by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology.[5][2] The Expert Panel on Enzymes of the International Federation of Clinical Chemistry also used this name.[6][2] The older name is gamma-glutamyl transpeptidase (GGTP).[2]

Function

GGT is present in the cell membranes of many tissues, including the kidneys, bile duct, pancreas, gallbladder, spleen, heart, brain, and seminal vesicles.[7] It is involved in the transfer of amino acids across the cellular membrane[8] and leukotriene metabolism.[9] 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.[10][11] This general reaction is:

(5-L-glutamyl)-peptide + an amino acid ⇌ peptide + 5-L-glutamyl amino acid

Structure

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. Latent elevations in GGT are typically seen in patients with chronic viral hepatitis infections often taking 12 months or more to present.

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 are conflicting data about whether GGT has better sensitivity.[12][13] 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.[13] 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,[14] suggesting a potential role in pathogenesis of cardiovascular diseases,[15] and circulates in blood in the form of distinct protein aggregates,[16] some of which appear to be related to specific pathologies such as metabolic syndrome, alcohol addiction and chronic liver disease.

GGT is elevated by ingestion of large quantities of alcohol. However, determination of high levels of total serum GGT activity is not specific to alcohol intoxication,[17] and the measurement of selected serum forms of the enzyme offer more specific information.[16] Isolated elevation or disproportionate elevation compared to other liver enzymes (such as ALT or alanine transaminase) can indicate alcohol abuse or alcoholic liver disease,[18] and can indicate excess alcohol consumption up to 3 or 4 weeks prior to the test. The mechanism for this elevation is unclear. Alcohol might increase GGT production by inducing hepatic microsomal production, or it might cause the leakage of GGT from hepatocytes.[19]

Numerous drugs can raise GGT levels, including barbiturates and phenytoin.[20] GGT elevation has also been occasionally reported following nonsteroidal anti-inflammatory drugs (including aspirin), St. John's wort and kava.[21] Elevated levels of GGT can also be due to congestive heart failure.[22]

Individual test results should always be interpreted using the reference range from the laboratory that performed the test, though example reference ranges are 15-85 IU/L for men, and 5-55 IU/L for women.[23]

Examples

Human proteins that belong to this family include GGT1, GGT2, GGT6, GGTL3, GGTL4, GGTLA1 and GGTLA4.

gollark: People do *tend* to focus on relatively insignificant bad things and ignore stuff mostly being fine and getting better.
gollark: So surely a murderer should be able to catch all lesser criminals.
gollark: There's that saying about how you set thieves to catch thieves.
gollark: Æ is no mere ligature. It is the ash symbol. Apioid.
gollark: Hmm, what if you could somehow *transfer* thermal energy *into* the car *from* room?

References
  1. Tate SS, Meister A (1985). "gamma-Glutamyl transpeptidase from kidney". Methods in Enzymology. 113: 400–19. doi:10.1016/S0076-6879(85)13053-3. ISBN 978-0-12-182013-8. PMID 2868390.
  2. Whitfield JB (August 2001). "Gamma glutamyl transferase". Critical Reviews in Clinical Laboratory Sciences. 38 (4): 263–355. doi:10.1080/20014091084227. PMID 11563810.
  3. Courtay C, Oster T, Michelet F, Visvikis A, Diederich M, Wellman M, Siest G (June 1992). "Gamma-glutamyltransferase: nucleotide sequence of the human pancreatic cDNA. Evidence for a ubiquitous gamma-glutamyltransferase polypeptide in human tissues". Biochemical Pharmacology. 43 (12): 2527–33. doi:10.1016/0006-2952(92)90140-E. PMID 1378736.
  4. Dominici S, Paolicchi A, Corti A, Maellaro E, Pompella A (2005). "Prooxidant reactions promoted by soluble and cell-bound gamma-glutamyltransferase activity". Methods in Enzymology. 401: 484–501. doi:10.1016/S0076-6879(05)01029-3. ISBN 9780121828066. PMID 16399404.
  5. "EC 2.3.2.2". International Union of Biochemistry and Molecular Biology. 2011. Retrieved 9 October 2016.
  6. Shaw LM, Strømme JH, London JL, Theodorsen L (December 1983). "International Federation of Clinical Chemistry. Scientific Committee, Analytical Section. Expert Panel on Enzymes. IFCC methods for measurement of enzymes. Part 4. IFCC methods for gamma-glutamyltransferase [(gamma-glutamyl)-peptide: amino acid gamma-glutamyltransferase, EC 2.3.2.2]. IFCC Document, Stage 2, Draft 2, 1983-01 with a view to an IFCC Recommendation". Clinica Chimica Acta; International Journal of Clinical Chemistry. 135 (3): 315F–338F. doi:10.1016/0009-8981(83)90291-7. PMID 6141014.
  7. Goldberg DM (1980). "Structural, functional, and clinical aspects of gamma-glutamyltransferase". CRC Critical Reviews in Clinical Laboratory Sciences. 12 (1): 1–58. doi:10.3109/10408368009108725. PMID 6104563.
  8. Meister A (August 1974). "The gamma-glutamyl cycle. Diseases associated with specific enzyme deficiencies". Annals of Internal Medicine. 81 (2): 247–53. doi:10.7326/0003-4819-81-2-247. PMID 4152527.
  9. 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.
  10. 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". Biochemical and Biophysical Research Communications. 65 (1): 68–74. doi:10.1016/S0006-291X(75)80062-3. PMID 238530.
  11. Yokoyama H (June 2007). "[Gamma glutamyl transpeptidase (gammaGTP) in the era of metabolic syndrome]". Nihon Arukōru Yakubutsu Igakkai Zasshi = Japanese Journal of Alcohol Studies & Drug Dependence (in Japanese). 42 (3): 110–24. PMID 17665541.
  12. Betro MG, Oon RC, Edwards JB (November 1973). "Gamma-glutamyl transpeptidase in diseases of the liver and bone". American Journal of Clinical Pathology. 60 (5): 672–8. doi:10.1093/ajcp/60.5.672. PMID 4148049.
  13. Lum G, Gambino SR (April 1972). "Serum gamma-glutamyl transpeptidase activity as an indicator of disease of liver, pancreas, or bone". Clinical Chemistry. 18 (4): 358–62. PMID 5012259.
  14. Emdin M, Pompella A, Paolicchi A (October 2005). "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.
  15. Pompella A, Emdin M, Passino C, Paolicchi A (2004). "The significance of serum gamma-glutamyltransferase in cardiovascular diseases". Clinical Chemistry and Laboratory Medicine. 42 (10): 1085–91. doi:10.1515/CCLM.2004.224. PMID 15552264.
  16. Franzini M, Bramanti E, Ottaviano V, Ghiri E, Scatena F, Barsacchi R, Pompella A, Donato L, Emdin M, Paolicchi A (March 2008). "A high performance gel filtration chromatography method for gamma-glutamyltransferase fraction analysis". Analytical Biochemistry. 374 (1): 1–6. doi:10.1016/j.ab.2007.10.025. PMID 18023410.
  17. 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 (2): 169–73. doi:10.1016/0009-8981(74)90225-3. PMID 4154814.
  18. Kaplan MM, et al. (1985). "Biochemical basis for serum enzyme abnormalities in alcoholic liver disease". In Chang NC, Chan NM (eds.). Early identification of alcohol abuse. Research Monograph No. 17. NIAAA. p. 186.
  19. 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.
  20. 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.
  21. "Kava Uses, Benefits & Dosage". Herbal Database. Drugs.com.
  22. 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.
  23. Mannion CM (2012). General Laboratory Manual (PDF). Department of Pathology, Hackensack University Medical Centre. p. 129. Retrieved 20 February 2014.


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