γ-glutamyl transferases

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γ-glutamyl transferase
Secondary to quaternary structure Heterodimer, membrane protein
Enzyme classification
EC, category 2.3.2.2 ,  transferase
Substrate 5-L-glutamyl peptide + amino acid
Products Peptide + 5-L-glutamyl amino acid

γ-Glutamyltransferases ( γ-GT pronounced: 'Gamma-GT', GGT , also γ-Glutamyltranspeptidasen , γ-GTP ) are a group of enzymes in many body cells of mammals , fungi and bacteria . They are part of the defense against reactive oxygen species .

Biochemical function

GGT transfers the glutamyl residue of glutathione to peptides or water. This simultaneously initiates the breakdown of glutathione (GSH). This degradation is the only way to smuggle the cysteine contained in GSH effectively and without loss into the cell, since there is no GSH membrane transporter . GSH is rebuilt within the cell.

The second reaction path, of which the reaction catalyzed by GGT is a part, is the discharge of foreign substances that have been bound in the cell by GSH (on the thiol group ). Here, the removal of the glutamate from the GSH part increases the transportability of the adduct so that it can be discharged .

Importance in medicine

GGT serves as a biomarker that indicates liver disease in connection with other values. Elevated GGT levels occur in biliary atresia and bacteremia .

Increased GGT values ​​correlate with an increased risk of later type 2 diabetes and cardiovascular diseases , as well as with increased homocysteine concentration.

Mutations in GGT can cause the (rare) glutathionuria .

Occurrence in humans

At least thirteen genes are known in humans which code for a GGT , of which at least six are active, each with several isoforms . Several isoforms of GGT are inactive in humans. One isoform of GGT7 binds to FAM57A. GGT5 converts leukotriene C4 to leukotriene  D4 and shows a changed substrate affinity. GGT3 is found in some epilepsy patients.

Gene name UniProt Size
UE1 + UE2 = total		 Isoforms OMIM Remarks
GGT1 P19440 380 + 189 = 569 3 612346 In the kidneys , liver , pancreas , stomach , intestines , placenta , lungs . Isoform 3 inactive. If mutated, glutathionuria .
GGT2 P36268 380 + 189 = 569 2 137181 In fetal / adult kidney and liver.
GGT3P A6NGU5 380 + 188 = 568 1 - Possibly inactive.
GGT5 P36269 387 + 998 = 586 2 137168 May not react with GSH but with GSH conjugate. Catalyzes leukotriene C4 = D4.
GGT6 Q6P531 ? +? = 493 2 612341 The substrate is GSH conjugate.
GGT7 Q9UJ14 472 + 190 = 662 4th 612342 Ubiquitously in small amounts, except in epithelial cells of the respiratory tract . The substrate is GSH conjugate.

Laboratory diagnostics

Liver diagnostics

In laboratory diagnostics , the activity of the GGT is determined from the plasma or the serum in order to clarify whether a liver or biliary tract disease is present. The reference range for measurements at 37 ° C (GGT37) according to IFCC is below 42 U / l for women and below 60 U / l for men.

The laboratory value GGT, which is measured in the blood , corresponds to the total enzymatic GGT activity, whereby it is assumed that measurable increases result exclusively from the destruction of liver cells , since it is an enzyme that is normally firmly bound to the cell membrane .

However, increased GGT values ​​can have many causes and must be interpreted in connection with other laboratory values ​​such as alkaline phosphatase , ALT / GPT , AST / GOT or bilirubin . Slight increases can occur from the use of certain medications or from chronic alcohol consumption. Stronger increases are found in chronic hepatitis , liver cirrhosis , liver metastases or damage to the liver from poisons , drugs, alcohol consumption or hereditary diseases such as myotonic dystrophy type 2 (DM2, PROMM). The highest GGT values ​​are observed in diseases of the biliary tract ( cholestasis , cholangitis ), in acute hepatitis and in toxic liver damage.

Kidney diagnostics

In the human kidney, GGT occurs in the highest concentration in the proximal tubule. There it is localized on the membrane surface of the microvilli (brush border) of the epithelia, i.e. directed towards the lumen. The GGT occurs here in the combination of a so-called multi-enzyme complex, which u. a. an alanine aminopeptidase and alkaline phosphatase also belong. The multi-enzyme complex consists of about 5 to 10 nm large stalked "balls" ( knobs ), which disintegrate from the membrane ( shedding ) and in increased concentration in the urine even with early damage to the kidneys (ischemia, nephrotoxins, inflammation or kidney transplant rejection ) of the sick appear (tissue proteinuria, histuria). The kidney-typical GGT, a glycoprotein with a lectin affinity for ConA and wheat-germ agglutinin, can be extracted from the urine of patients with kidney diseases e.g. B. isolate by immunospecific affinity chromatography. The GGT is an important differentiation marker of tubular kidney cells, whereby the GGT biosynthesis is adapted depending on the kidney function: for example, hypertrophied (and hypermetabolic) nephrons in chronic kidney failure increasingly express membrane-bound GGT.

Renal adenocarcinoma: the membrane-bound GGT is - regardless of the tumor differentiation - a constant membrane marker of clear cell renal adenocarcinomas. A monoclonal antibody against a tumor-associated GGT, now also available recombinantly , was used for immunoscintigraphic purposes and immunohistological diagnosis of metastases.

literature

  • B. Neumeister, I. Besenthal, H. Liebrich: Clinical guidelines for laboratory diagnostics. Urban & Fischer, Munich / Jena 2003, ISBN 3-437-22231-7 .
  • Lothar Thomas: Laboratory and Diagnosis. TH-Books, Frankfurt am Main 2005, ISBN 3-9805215-5-9 .

Web links

Wikibooks: Biochemistry and Pathobiochemistry: Arachidonic Acid Metabolism  - Learning and Teaching Materials
Wikibooks: Biochemistry and Pathobiochemistry: Glutathione Metabolism  - Learning and Teaching Materials

Individual evidence

  1. ↑ Kuo-Shu Tang, Li-Tung Huang, Ying-Hsien Huang, Chi-Yin Lai, Chi-Hung Wu, Sheng-Ming Wang, Kao-Pin Hwang, Fu-Chen Huang, Mao-Meng Tiao: Gamma-glutamyl transferase in the diagnosis of biliary atresia . In: Acta Paediatrica Taiwanica = Taiwan Er Ke Yi Xue Hui Za Zhi . tape 48 , 4 (July-August), 2007, ISSN  1608-8115 , pp. 196-200 , PMID 18265540 .
  2. ↑ Shinichiro Kanai, Takayuki Honda, Takeshi Uehara, Takehisa Matsumoto: Liver function tests in patients with bacteremia . In: Journal of Clinical Laboratory Analysis . tape 22 , no. 1 , 2008, ISSN  0887-8013 , p. 66-69 , doi : 10.1002 / jcla.20205 , PMID 18200569 .
  3. ↑ DH Lee, MW Steffes, DR Jacobs: Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes? In: Diabetologia . Volume 51, Number 3, March 2008, pp. 402-407, doi: 10.1007 / s00125-007-0896-5 . PMID 18071669 .
  4. ↑ E. Ruttmann, LJ Brant and a .: Gamma-glutamyltransferase as a risk factor for cardiovascular disease mortality: an epidemiological investigation in a cohort of 163,944 Austrian adults. In: Circulation . Volume 112, number 14, October 2005, pp. 2130-2137, doi: 10.1161 / CIRCULATIONAHA.105.552547 . PMID 16186419 .
  5. ↑ UniProt P19440
  6. ↑ G. Lippi, GL Salvagno u. a .: Plasma gamma-glutamyl transferase activity predicts homocysteine ​​concentration in a large cohort of unselected outpatients. In: Internal medicine. Volume 47, Number 8, 2008, pp. 705-707, PMID 18421185 .
  7. ↑ UniProt Q9UJ14
  8. ↑ UniProt P36269
  9. ↑ UniProt A6NGU5
  10. ↑ Lab Tests Online: GGT
  11. ↑ N. Heisterkamp, ​​J. Groffen u. a .: The human gamma-glutamyl transferase gene family. In: Human genetics. Volume 123, Number 4, May 2008, pp. 321-332, doi: 10.1007 / s00439-008-0487-7 . PMID 18357469 .
  12. ↑ GB Wolf, JE Scherberich, W. Schoeppe: Peptidase-associated antigens as markers of differentiation in human kidney and renal adenocarcinoma. In: Cellular and molecular biology. Volume 34, Number 3, 1988, pp. 311-321, PMID 3061652 .
  13. ^ JE Scherberich, WA Mondorf: Excretion of kidney brush border antigens as a quantitative indicator of tubular damage. In: Current problems in clinical biochemistry. Number 9, 1979, pp. 281-298, PMID 36259 .
  14. ^ JE Scherberich, B. Kleemann, W. Mondorf: Isolation of kidney brush border gamma-glutamyl transpeptidase from urine by specific antibody gel chromatography. In: Clinica Chimica Acta . Volume 93, Number 1, April 1979, pp. 35-41, PMID 35293 .
  15. ↑ JE Scherberich, G. Wolf u. a .: Glomerular and tubular membrane antigens reflecting cellular adaptation in human renal failure. In: Kidney International . Supplement. Volume 27, November 1989, pp. S38-S51, PMID 2636672 .
  16. ↑ P. Fischer, S. Störkel u. a .: Differential diagnosis of histogenetically distinct human epithelial renal tumors with a monoclonal antibody against gamma-glutamyltransferase. In: Cancer Immunology, Immunotherapy . Volume 33, Number 6, 1991, pp. 382-388, PMID 1678984 .
  17. ↑ P. Fischer, JE Scherberich, W. Schoeppe: Comparative biochemical and immunological studies on gamma-glutamyltransferases from human kidney and renal cell carcinoma applying monoclonal antibodies. In: Clinica Chimica Acta . Volume 191, Number 3, November 1990, pp. 185-200, PMID 1979761 .
  18. ↑ O. Kaufmann, M. Dietel u. a .: Immunohistochemical differentiation of metastases of renal carcinomas versus other carcinomas with anti-gamma GT monoclonal antibody 138H11. In: Histopathology . Volume 31, Number 1, July 1997, pp. 31-37, PMID 9253622 .
  19. ↑ P. Fischer, RP Baum u. a .: Immunoscintigraphic localization of renal tumors in an extracorporeal perfusion model with a monoclonal antibody against gamma-glutamyltransferase. In: Cancer Immunology, Immunotherapy . Volume 35, Number 4, 1992, pp. 283-288, PMID 1355011 .
  20. ↑ K. Knoll, W. Wrasidlo et al. a .: Targeted therapy of experimental renal cell carcinoma with a novel conjugate of monoclonal antibody 138H11 and calicheamicin thetaI1. In: Cancer Research . Volume 60, Number 21, November 2000, pp. 6089-6094, PMID 11085532 .
  21. ↑ A. Schmiedl, J. Zimmermann u. a .: Recombinant variants of antibody 138H11 against human gamma-glutamyltransferase for targeting renal cell carcinoma. In: Human antibodies. Volume 15, Number 3, 2006, pp. 81-94, PMID 17065739 .