Gamma-glutamyl transpeptidase

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Gamma-glutamyltranspeptidase
Identifiers
SymbolG_glu_transpept
PfamPF01019
InterProIPR000101
PROSITEPDOC00404
 
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Not to be confused with GGGT.
Gamma-glutamyltranspeptidase
Identifiers
SymbolG_glu_transpept
PfamPF01019
InterProIPR000101
PROSITEPDOC00404
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 / EGO
gamma-glutamyltransferase 1
Identifiers
SymbolGGT1
Alt. symbolsGGT
Entrez2678
HUGO4250
OMIM231950
RefSeqNM_001032364
UniProtP19440
Other data
LocusChr. 22 q11.1-11.2
gamma-glutamyltransferase 2
Identifiers
SymbolGGT2
Alt. symbolsGGT
Entrez2679
HUGO4251
OMIM137181
RefSeqNM_002058
UniProtP36268
Other data
LocusChr. 22 q11.1-11.2

Gamma-glutamyl transferase or gamma-glutamyl transpeptidase (also γ-glutamyl transferase, 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[edit]

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[edit]

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[edit]

GGT is predominantly used as a diagnostic marker for liver disease in medicine, latent elevations in GGT are typically seen in patients with chronic viral hepatitis infections often taking 12 months or more to present.[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.[9]

GGT is elevated by large quantities of alcohol ingestion. Determination of total serum GGT activity is however not specific to alcohol intoxication,[15] 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.[16] 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.[17]

Numerous drugs can raise GGT levels, including barbiturates and phenytoin.[18] 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.[19]

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.[20]

Human proteins[edit]

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

References[edit]

  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. doi:10.7326/0003-4819-81-2-247. 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. ^ a b 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. 
  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. ^ 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. doi:10.1016/0009-8981(74)90225-3. 
  16. ^ Kaplan MM, et al. (1985). Chang NC, Chan NM, ed. Biochemical basis for serum enzyme abnormalities in alcoholic liver disease. Research Monograph No. 17 (in Early identification of alcohol abuse) (NIAAA). p. 186. 
  17. ^ 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. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ General Laboratory Manual. Department of Pathology, Hackensack University Medical Centre. 2012. p. 129. Retrieved 20 Feb 2014. 

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