Biology:Gamma-glutamyltransferase

From HandWiki
Short description: Class of enzymes
Gamma-glutamyl transpeptidase
Identifiers
SymbolG_glu_transpept
PfamPF01019
InterProIPR000101
PROSITEPDOC00404
Membranome274
Gamma-glutamyltransferase
GGT structure.png
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

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.

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

Biochemistry

In prokaryotes and eukaryotes, GGT consists of two polypeptide chains, a heavy and a light subunit, processed from a single chain precursor by an autocatalytic cleavage.[12] The active site of GGT is known to be located in the light subunit.[citation needed]

Co-translational N-glycosylation serves a significant role in the proper autocatalytic cleavage and proper folding of GGT. Single site mutations at asparagine residues were shown to result in a functionally active yet slightly less thermally stable version of the enzyme in vitro, while knockout of all asparagine residues resulted in an accumulation of the uncleaved, propeptide form of the enzyme.[12]

Clinical significance

GGT is predominantly used as a diagnostic marker for liver disease.[citation needed] Elevated serum GGT activity can be found in diseases of the liver, biliary system, pancreas and kidneys.[13][14] Latent elevations in GGT are typically seen in patients with chronic viral hepatitis infections often taking 12 months or more to present.[citation needed]

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.[15] GGT 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.[16][17] In general, ALP is still the first test for biliary disease. The main value of GGT over ALP is in verifying that GGT elevations are, in fact, due to biliary disease; ALP can also be increased in certain bone diseases, but GGT is not.[17]

Alcohol use

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,[18] and the measurement of selected serum forms of the enzyme offer more specific information.[19] Isolated elevation or disproportionate elevation compared to other liver enzymes (such as ALT or alanine transaminase) can indicate harmful alcohol use or alcoholic liver disease,[20] 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.[21]

Xenobiotics

Numerous drugs can raise GGT levels, including barbiturates and phenytoin.[22] GGT elevation has also been occasionally reported following nonsteroidal anti-inflammatory drugs (including aspirin), St. John's wort and kava.[23]

Cardiovascular disease

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,[24] suggesting a potential role in pathogenesis of cardiovascular diseases,[25] and circulates in blood in the form of distinct protein aggregates,[19] some of which appear to be related to specific pathologies such as metabolic syndrome, alcohol addiction and chronic liver disease.

Elevated levels of GGT can also be due to congestive heart failure.[26]

Neoplasms

GGT is expressed in high levels in many different tumors. It is known to accelerate tumor growth and to increase resistance to cisplatin in tumors.[27]

Examples

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

References

  1. ↑ 1.0 1.1 "[50] γ-Glutamyl transpeptidase from kidney". gamma-Glutamyl transpeptidase from kidney. Methods in Enzymology. 113. 1985. pp. 400–19. doi:10.1016/S0076-6879(85)13053-3. ISBN 978-0-12-182013-8. https://archive.org/details/glutamateglutami0000unse/page/400. 
  2. ↑ 2.0 2.1 2.2 2.3 "Gamma glutamyl transferase". Critical Reviews in Clinical Laboratory Sciences 38 (4): 263–355. August 2001. doi:10.1080/20014091084227. PMID 11563810. 
  3. ↑ "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. June 1992. doi:10.1016/0006-2952(92)90140-E. PMID 1378736. 
  4. ↑ "Prooxidant Reactions Promoted by Soluble and Cell-Bound γ-Glutamyltransferase Activity". Prooxidant reactions promoted by soluble and cell-bound gamma-glutamyltransferase activity. Methods in Enzymology. 401. 2005. pp. 484–501. doi:10.1016/S0076-6879(05)01029-3. ISBN 9780121828066. https://archive.org/details/gluthionetransfe00sies/page/484. 
  5. ↑ "EC 2.3.2.2". International Union of Biochemistry and Molecular Biology. 2011. http://www.chem.qmul.ac.uk/iubmb/enzyme/EC2/3/2/2.html. 
  6. ↑ "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. December 1983. doi:10.1016/0009-8981(83)90291-7. PMID 6141014. 
  7. ↑ "Structural, functional, and clinical aspects of gamma-glutamyltransferase". CRC Critical Reviews in Clinical Laboratory Sciences 12 (1): 1–58. 1980. doi:10.3109/10408368009108725. PMID 6104563. 
  8. ↑ "The gamma-glutamyl cycle. Diseases associated with specific enzyme deficiencies". Annals of Internal Medicine 81 (2): 247–53. August 1974. doi:10.7326/0003-4819-81-2-247. PMID 4152527. 
  9. ↑ "Metabolism of leukotrienes by L-gamma-glutamyl-transpeptidase and dipeptidase from human polymorphonuclear granulocytes". Immunology 55 (1): 135–47. May 1985. PMID 2860060. 
  10. ↑ "Glutathionuria: inborn error of metabolism due to tissue deficiency of gamma-glutamyl transpeptidase". Biochemical and Biophysical Research Communications 65 (1): 68–74. July 1975. doi:10.1016/S0006-291X(75)80062-3. PMID 238530. 
  11. ↑ "[Gamma glutamyl transpeptidase (gammaGTP) in the era of metabolic syndrome]" (in ja). Nihon Arukōru Yakubutsu Igakkai Zasshi = Japanese Journal of Alcohol Studies & Drug Dependence 42 (3): 110–24. June 2007. PMID 17665541. 
  12. ↑ 12.0 12.1 West, Matthew B.; Wickham, Stephanie; Quinalty, Leslie M.; Pavlovicz, Ryan E.; Li, Chenglong; Hanigan, Marie H. (2011-08-19). "Autocatalytic cleavage of human gamma-glutamyl transpeptidase is highly dependent on N-glycosylation at asparagine 95". The Journal of Biological Chemistry 286 (33): 28876–28888. doi:10.1074/jbc.M111.248823. ISSN 1083-351X. PMID 21712391. 
  13. ↑ Fine, A.; McIntosh, W. B. (May 1975). "Elevation of Serum Gamma-Glutamyl Transpeptidase in End-Stage Chronic Renal Failure" (in en). Scottish Medical Journal 20 (3): 113–115. doi:10.1177/003693307502000309. ISSN 0036-9330. PMID 242073. http://journals.sagepub.com/doi/10.1177/003693307502000309. 
  14. ↑ Endre, Zoltán H.; Pickering, John W.; Walker, Robert J.; Devarajan, Prasad; Edelstein, Charles L.; Bonventre, Joseph V.; Frampton, Christopher M.; Bennett, Michael R. et al. (2011-05-02). "Improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function" (in en). Kidney International 79 (10): 1119–1130. doi:10.1038/ki.2010.555. ISSN 0085-2538. PMID 21307838. 
  15. ↑ Mannion, Ciaran M. (2012). General Laboratory Manual. Department of Pathology, Hackensack University Medical Centre. p. 129. http://www.hackensackumc.org/assets/1/7/General_Laboratory_Manual.pdf. Retrieved 20 February 2014. 
  16. ↑ "Gamma-glutamyl transpeptidase in diseases of the liver and bone". American Journal of Clinical Pathology 60 (5): 672–8. November 1973. doi:10.1093/ajcp/60.5.672. PMID 4148049. 
  17. ↑ 17.0 17.1 "Serum gamma-glutamyl transpeptidase activity as an indicator of disease of liver, pancreas, or bone". Clinical Chemistry 18 (4): 358–62. April 1972. doi:10.1093/clinchem/18.4.358. PMID 5012259. 
  18. ↑ "Determination de la gamma-glutamyl transpeptidase senque des ethyliques a la suite du sevrage". Clin Chim Acta 56 (2): 169–73. 1974. doi:10.1016/0009-8981(74)90225-3. PMID 4154814. 
  19. ↑ 19.0 19.1 "A high performance gel filtration chromatography method for gamma-glutamyltransferase fraction analysis". Analytical Biochemistry 374 (1): 1–6. March 2008. doi:10.1016/j.ab.2007.10.025. PMID 18023410. 
  20. ↑ "Biochemical basis for serum enzyme abnormalities in alcoholic liver disease". Early identification of alcohol abuse. NIAAA. 1985. p. 186. 
  21. ↑ "Ethanol effects in a rat hepatoma cell line: induction of gamma-glutamyltransferase". Hepatology 3 (3): 323–9. 1983. doi:10.1002/hep.1840030308. PMID 6132864. 
  22. ↑ "Plasma gamma-glutamyl transpeptidase elevation in patients receiving enzyme-inducing drugs". Lancet 2 (7720): 376–7. August 1971. doi:10.1016/S0140-6736(71)90093-6. PMID 4105075. 
  23. ↑ "Kava Uses, Benefits & Dosage". Herbal Database. Drugs.com. https://www.drugs.com/npp/kava.html. 
  24. ↑ "Gamma-glutamyltransferase, atherosclerosis, and cardiovascular disease: triggering oxidative stress within the plaque". Circulation 112 (14): 2078–80. October 2005. doi:10.1161/CIRCULATIONAHA.105.571919. PMID 16203922. 
  25. ↑ "The significance of serum gamma-glutamyltransferase in cardiovascular diseases". Clinical Chemistry and Laboratory Medicine 42 (10): 1085–91. 2004. doi:10.1515/CCLM.2004.224. PMID 15552264. 
  26. ↑ "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. October 2005. doi:10.1161/CIRCULATIONAHA.105.552547. PMID 16186419. 
  27. ↑ Hanigan, M. H.; Gallagher, B. C.; Townsend, D. M.; Gabarra, V. (April 1999). "Gamma-glutamyl transpeptidase accelerates tumor growth and increases the resistance of tumors to cisplatin in vivo". Carcinogenesis 20 (4): 553–559. doi:10.1093/carcin/20.4.553. ISSN 0143-3334. PMID 10223181. 

External links



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Gamma-glutamyltransferase&oldid=3592394"