GNMT

Glycine N-methyltransferase is an enzyme that in humans is encoded by the GNMT gene.[5][6][7]

GNMT
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGNMT, HEL-S-182mP, glycine N-methyltransferase
External IDsOMIM: 606628 MGI: 1202304 HomoloGene: 7741 GeneCards: GNMT
Gene location (Human)
Chr.Chromosome 6 (human)[1]
Band6p21.1Start42,960,754 bp[1]
End42,963,880 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

27232

14711

Ensembl

ENSG00000124713

ENSMUSG00000002769

UniProt

Q14749

Q9QXF8

RefSeq (mRNA)

NM_018960
NM_001318865

NM_010321
NM_001364890

RefSeq (protein)

NP_001305794
NP_061833

NP_034451
NP_001351819

Location (UCSC)Chr 6: 42.96 – 42.96 MbChr 17: 46.73 – 46.73 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Discovery

The enzyme was first described by Blumenstein and Williams (1960) in guinea pig liver.[8] However, this enzyme was not purified until 1972 in the rabbit liver by Kerr.[9] In 1984, Cook and Wagner demonstrated that a liver cytosolic folate binding protein is identical to GNMT.[10] The human GMNT gene was cloned in 2000 by Chen and coworkers.[6]

Tissue distribution

GNMT is an abundant enzyme in liver cytosol and consists of 0.9% to 3% of the soluble protein present in liver.[11] In addition to liver, GNMT activity has been found in a number of other tissues including pancreas and kidney.[9] GNMT is most abundant in the peri-portal region of the liver and exocrine tissue of the pancreas.[11] The GNMT proteins located in tissues that are actively in secretion, such as the proximal kidney tubules, the submaxillary glands and the intestinal mucosa.[11] GNMT is also expressed in various neurons presented in the cerebral cortex, hippocampus, substantia nigra and cerebellum.[12] 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.[11][13][14][15][16] 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.[15] The structure of recombinant rat, mouse and human GNMTs have been solved.[17][18] 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)[19] and participates in the detoxification pathway in liver cells.[7] 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.[9] GNMT regulates the relative levels of SAM and SAH. Since SAM is the methyl donor for almost all cellular methylation reactions.[19] GNMT is therefore likely to regulate cellular methylation capacity.[19][20] An endogenous ligand of GNMT, 5-methyltetrahydropteroylpentaglutamate (5-CH3-H4PteGIu5) is a powerful inhibitor of this enzyme.[21] 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.[19][21]

In addition to the methyltransferase activity, the 4S polycyclic aromatic hydrocarbon (PAH)-binding protein and GNMT are one and the same protein.[22] The catalytic site resembles a molecular basket, unlike most other SAM-dependent methyltransferases,[17] 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.[23]

Clinical significance

GNMT has been shown to detoxify some environmental carcinogens such as polyaromatic hydrocarbons and aflatoxin.[24]

There is mounting evidence that supports the involvement of GNMT deficiency in liver carcinogenesis.[25]

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.[26]

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References
  1. GRCh38: Ensembl release 89: ENSG00000124713 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000002769 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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.
  6. 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.
  7. "Entrez Gene: GNMT glycine N-methyltransferase".
  8. 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.
  9. Kerr SJ, Borek E (1972). "The tRNA methyltransferases". Advances in Enzymology and Related Areas of Molecular Biology. Advances in Enzymology and Related Areas of Molecular Biology. 36. pp. 1–27. doi:10.1002/9780470122815.ch1. ISBN 9780470122815. PMID 4563428.
  10. 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. Bibcode:1984PNAS...81.3631C. doi:10.1073/pnas.81.12.3631. PMC 345272. PMID 6587377.
  11. 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. Bibcode:1994PNAS...91..210Y. doi:10.1073/pnas.91.1.210. PMC 42916. PMID 8278367.
  12. 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.
  13. Heady JE, Kerr SJ (1973). "Purification and characterization of glycine N-methyltransferase". The Journal of Biological Chemistry. 248 (1): 69–72. PMID 4692843.
  14. 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.
  15. 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.
  16. Yeo EJ, Wagner C (1992). "Purification and properties of pancreatic glycine N-methyltransferase". The Journal of Biological Chemistry. 267 (34): 24669–74. PMID 1332963.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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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