GNMT

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This article is about the enzyme. For the machine translation system, see GNMT (translation).
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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Glycine N-methyltransferase is an enzyme that in humans is encoded by the GNMT gene.[1][2][3]

Discovery

The enzyme was first described by Blumenstein and Williams (1960) in guinea pig liver.[4] However, this enzyme was not purified until 1972 in the rabbit liver by Kerr.[5] In 1984, Cook and Wagner demonstrated that a liver cytosolic folate binding protein is identical to GNMT.[6] The human GMNT gene was cloned in 2000 by Chen and coworkers.[2]

Tissue distribution

GNMT is an abundant enzyme in liver cytosol and consists of 0.9% to 3% of the soluble protein present in liver.[7] In addition to liver, GNMT activity has been found in a number of other tissues including pancreas and kidney.[5] GNMT is most abundant in the peri-portal region of the liver and exocrine tissue of the pancreas.[7] The GNMT proteins located in tissues that are actively in secretion, such as the proximal kidney tubules, the submaxillary glands and the intestinal mucosa.[7] GNMT is also expressed in various neurons presented in the cerebral cortex, hippocampus, substantia nigra and cerebellum.[8] The presence of GNMT in these cells suggests that this enzyme may play a role in secretion.

Structure

The properties of GNMT protein from rabbits, rats and humans, either purified from liver/pancreas, or expressed in Escherichia coli, have been well characterized. All GNMTs have very similar molecular and kinetic properties.[7][9][10][11][12] Comparison of the cDNA and protein sequences of human, rabbit, pig and rat GNMTs shows similarities of over 84% at the nucleotide level and about 90% at the amino acid level. All GNMTs are 130 kDa tetramers consisting of four identical subunits, each having a Mr of 32 kDa.[11] The structure of recombinant rat, mouse and human GNMTs have been solved.[13][14] The four nearly spherical subunits are arranged to form a flat and square tetramer with a large hole in the center. The active sites are located in the near center of each subunit.

Function

Glycine N-methyltransferase catalyzes the synthesis of N-methylglycine (sarcosine) from glycine using S-adenosylmethionine(SAM) (AdoMet) as the methyl donor. GNMT acts as an enzyme to regulate the ratio of S-adenosylmethionine(SAM) to S-adenosylhomocysteine (SAH) (AdoHcy)[15] and participates in the detoxification pathway in liver cells.[3] GNMT competes with tRNA methyltransferases for SAM and the product, S-adenosylhomocysteine (SAH), is a potent inhibitor of tRNA methyltransferases and a relatively weak inhibitor of GNMT.[5] GNMT regulates the relative levels of SAM and SAH. Since SAM is the methyl donor for almost all cellular methylation reactions.[15] GNMT is therefore likely to regulate cellular methylation capacity.[15][16] An endogenous ligand of GNMT, 5-methyltetrahydropteroylpentaglutamate (5-CH3-H4PteGIu5) is a powerful inhibitor of this enzyme.[17] Thus, GNMT has been proposed to link the de novo synthesis of methyl groups to the ratio of SAM to SAH, which in turn serves as a bridge between methionine and one-carbon metabolism.[15][17]

In addition to the methyltransferase activity, the 4S polycyclic aromatic hydrocarbon (PAH)-binding protein and GNMT are one and the same protein.[18] The catalytic site resembles a molecular basket, unlike most other SAM-dependent methyltransferases,[13] which therefore suggests that GNMT may be capable of capturing unidentified chemicals as a part of a detoxification process. Therefore, GNMT has been proposed to be a protein with diverse functionality.[19]

Clinical significance

GNMT has been shown to detoxify some environmental carcinogens such as polyaromatic hydrocarbons and aflatoxin.[20]

There is mounting evidence that supports the involvement of GNMT deficiency in liver carcinogenesis.[21]

Inducer

The glycoside natural product 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranoside (PGG) isolated from Paeonia lactiflora, an Asian flower plant, induces GNMT mRNA and protein expression in Huh7 human hepatoma cells.[22]

References

  1. ↑ Chen YM, Shiu JY, Tzeng SJ, Shih LS, Chen YJ, Lui WY, Chen PH (March 1998). "Characterization of glycine-N-methyltransferase-gene expression in human hepatocellular carcinoma". International Journal of Cancer. 75 (5): 787–93. doi:10.1002/(SICI)1097-0215(19980302)75:5<787::AID-IJC20>3.0.CO;2-2. PMID 9495250.
  2. ↑ 2.0 2.1 Chen YM, Chen LY, Wong FH, Lee CM, Chang TJ, Yang-Feng TL (May 2000). "Genomic structure, expression, and chromosomal localization of the human glycine N-methyltransferase gene". Genomics. 66 (1): 43–7. doi:10.1006/geno.2000.6188. PMID 10843803.
  3. ↑ 3.0 3.1 "Entrez Gene: GNMT glycine N-methyltransferase".
  4. ↑ Blumenstein J, Williams GR (September 1960). "The enzymic N-methylation of glycine". Biochemical and Biophysical Research Communications. 3 (3): 259–263. doi:10.1016/0006-291X(60)90235-7.
  5. ↑ 5.0 5.1 5.2 Kerr SJ, Borek E (1972). "The tRNA methyltransferases". Advances in Enzymology and Related Areas of Molecular Biology. 36: 1–27. PMID 4563428.
  6. ↑ Cook RJ, Wagner C (1984). "Glycine N-methyltransferase is a folate binding protein of rat liver cytosol". Proceedings of the National Academy of Sciences of the United States of America. 81 (12): 3631–4. doi:10.1073/pnas.81.12.3631. PMC 345272. PMID 6587377.
  7. ↑ 7.0 7.1 7.2 7.3 Yeo EJ, Wagner C (1994). "Tissue distribution of glycine N-methyltransferase, a major folate-binding protein of liver". Proceedings of the National Academy of Sciences of the United States of America. 91 (1): 210–4. doi:10.1073/pnas.91.1.210. PMC 42916. PMID 8278367.
  8. ↑ Yang CP, Wang HA, Tsai TH, Fan A, Hsu CL, Chen CJ, Hong CJ, Chen YM (August 2012). "Characterization of the neuropsychological phenotype of glycine N-methyltransferase-/- mice and evaluation of its responses to clozapine and sarcosine treatments". European Neuropsychopharmacology. 22 (8): 596–606. doi:10.1016/j.euroneuro.2011.12.007. PMID 22264868.
  9. ↑ Heady JE, Kerr SJ (1973). "Purification and characterization of glycine N-methyltransferase". The Journal of Biological Chemistry. 248 (1): 69–72. PMID 4692843.
  10. ↑ Ogawa H, Fujioka M (1982). "Purification and properties of glycine N-methyltransferase from rat liver". The Journal of Biological Chemistry. 257 (7): 3447–52. PMID 6801046.
  11. ↑ 11.0 11.1 Ogawa H, Gomi T, Fujioka M (1993). "Mammalian glycine N-methyltransferases. Comparative kinetic and structural properties of the enzymes from human, rat, rabbit and pig livers". Comparative Biochemistry and Physiology. B, Comparative Biochemistry. 106 (3): 601–11. doi:10.1016/0305-0491(93)90137-t. PMID 8281755.
  12. ↑ Yeo EJ, Wagner C (1992). "Purification and properties of pancreatic glycine N-methyltransferase". The Journal of Biological Chemistry. 267 (34): 24669–74. PMID 1332963.
  13. ↑ 13.0 13.1 Fu Z, Hu Y, Konishi K, Takata Y, Ogawa H, Gomi T, Fujioka M, Takusagawa F (1996). "Crystal structure of glycine N-methyltransferase from rat liver". Biochemistry. 35 (37): 11985–93. doi:10.1021/bi961068n. PMID 8810903.
  14. ↑ Pakhomova S, Luka Z, Grohmann S, Wagner C, Newcomer ME (2004). "Glycine N-methyltransferases: a comparison of the crystal structures and kinetic properties of recombinant human, mouse and rat enzymes". Proteins. 57 (2): 331–7. doi:10.1002/prot.20209. PMID 15340920.
  15. ↑ 15.0 15.1 15.2 15.3 Luka Z, Mudd SH, Wagner C (2009). "Glycine N-methyltransferase and regulation of S-adenosylmethionine levels". The Journal of Biological Chemistry. 284 (34): 22507–11. doi:10.1074/jbc.R109.019273. PMC 2755656. PMID 19483083.
  16. ↑ McCabe DC, Caudill MA (2005). "DNA methylation, genomic silencing, and links to nutrition and cancer". Nutrition Reviews. 63 (6 Pt 1): 183–95. doi:10.1111/j.1753-4887.2005.tb00136.x. PMID 16028562.
  17. ↑ 17.0 17.1 Wagner C, Briggs WT, Cook RJ (1985). "Inhibition of glycine N-methyltransferase activity by folate derivatives: implications for regulation of methyl group metabolism". Biochemical and Biophysical Research Communications. 127 (3): 746–52. doi:10.1016/s0006-291x(85)80006-1. PMID 3838667.
  18. ↑ Raha A, Wagner C, MacDonald RG, Bresnick E (1994). "Rat liver cytosolic 4 S polycyclic aromatic hydrocarbon-binding protein is glycine N-methyltransferase". The Journal of Biological Chemistry. 269 (8): 5750–6. PMID 8119914.
  19. ↑ Bhat R, Bresnick E (August 1997). "Glycine N-methyltransferase is an example of functional diversity. Role as a polycyclic aromatic hydrocarbon-binding receptor". The Journal of Biological Chemistry. 272 (34): 21221–6. doi:10.1074/jbc.272.34.21221. PMID 9261130.
  20. ↑ Yen CH, Lin YT, Chen HL, Chen SY, Chen YM (January 2013). "The multi-functional roles of GNMT in toxicology and cancer". Toxicology and Applied Pharmacology. 266 (1): 67–75. doi:10.1016/j.taap.2012.11.003. PMID 23147572.
  21. ↑ Barić I (2009). "Inherited disorders in the conversion of methionine to homocysteine". Journal of Inherited Metabolic Disease. 32 (4): 459–71. doi:10.1007/s10545-009-1146-4. PMID 19585268.
  22. ↑ Kant R, Yen CH, Lu CK, Lin YC, Li JH, Chen YM (May 2016). "Identification of 1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranoside as a Glycine N-Methyltransferase Enhancer by High-Throughput Screening of Natural Products Inhibits Hepatocellular Carcinoma". International Journal of Molecular Sciences. 17 (5): 669. doi:10.3390/ijms17050669. PMC 4881495. PMID 27153064.

Further reading

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