Gamma-glutamyltransferase (also γ-glutamyltransferase, GGT, gamma-GT, gamma-glutamyl transpeptidase;[1]EC2.3.2.2) is a transferase (a type of enzyme) that catalyzes the transfer of gamma-glutamylfunctional 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]
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]
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 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.[17]
Alcohol use
GGT is elevated by ingestion of large quantities of alcohol (needs reference) 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.[citation needed] 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]
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.
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]
^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. PMID1378736.
^"EC 2.3.2.2". International Union of Biochemistry and Molecular Biology. 2011. Retrieved 9 October 2016.
^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. PMID6141014.
^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. PMID6104563.
^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. PMID4152527.
^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. PMID238530.
^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. PMID17665541.
^Mannion CM (2012). General Laboratory Manual(PDF). Department of Pathology, Hackensack University Medical Centre. p. 129. Retrieved 20 February 2014.
^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. PMID4148049.
^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. PMID4154814.
^ abFranzini 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. hdl:11382/3163. PMID18023410.
^Kaplan MM, Matloff DS, Selinger MJ, Quaroni EG (1985). "Biochemical basis for serum enzyme abnormalities in alcoholic liver disease". In Chang NC, Chao HM (eds.). Early identification of alcohol abuse, Proceedings of a workshop October 31–November 1, 1983. Rockville, Maryland: National Institute on Alcohol Abuse and Alcoholism. pp. 186–198. LCCN84601128. Research Monograph No. 17.
^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. PMID15552264. S2CID4248204.
^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. PMID16186419.
