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GNMT

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This article is about the enzyme. For the machine translation system, see GNMT (translation).Protein-coding gene in the species Homo sapiens
GNMT
Available structures
PDBOrtholog search: PDBe RCSB
List of PDB id codes

1R74, 2AZT

Identifiers
AliasesGNMT, HEL-S-182mP, glycine N-methyltransferase
External IDsOMIM: 606628; MGI: 1202304; HomoloGene: 7741; GeneCards: GNMT; OMA:GNMT - orthologs
Gene location (Human)
Chromosome 6 (human)
Chr.Chromosome 6 (human)
Chromosome 6 (human)Genomic location for GNMTGenomic location for GNMT
Band6p21.1Start42,960,754 bp
End42,963,880 bp
Gene location (Mouse)
Chromosome 17 (mouse)
Chr.Chromosome 17 (mouse)
Chromosome 17 (mouse)Genomic location for GNMTGenomic location for GNMT
Band17 22.9 cM|17 CStart47,036,590 bp
End47,040,094 bp
RNA expression pattern
Bgee
HumanMouse (ortholog)
Top expressed in
  • body of pancreas

  • right lobe of liver

  • body of stomach

  • prostate

  • olfactory zone of nasal mucosa

  • apex of heart

  • granulocyte

  • gastric mucosa

  • Pituitary Gland

  • anterior pituitary
Top expressed in
  • left lobe of liver

  • gallbladder

  • parotid gland

  • right kidney

  • vestibular membrane of cochlear duct

  • pyloric antrum

  • proximal tubule

  • human kidney

  • lip

  • submandibular gland
More reference expression data
BioGPS
More reference expression data
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
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: 47.04 – 47.04 Mb
PubMed search
Wikidata
View/Edit HumanView/Edit Mouse

Glycine N-methyltransferase is an enzyme that in humans is encoded by the GNMT gene.

Discovery

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

Tissue distribution

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

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

Clinical significance

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

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

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.

References

  1. ^ GRCh38: Ensembl release 89: ENSG00000124713Ensembl, May 2017
  2. ^ GRCm38: Ensembl release 89: ENSMUSG00000002769Ensembl, 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. S2CID 42285102.
  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. Vol. 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. S2CID 11604802.
  13. Heady JE, Kerr SJ (1973). "Purification and characterization of glycine N-methyltransferase". The Journal of Biological Chemistry. 248 (1): 69–72. doi:10.1016/S0021-9258(19)44446-3. 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. doi:10.1016/S0021-9258(18)34798-7. 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. doi:10.1016/S0021-9258(18)35816-2. 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. S2CID 26065465.
  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. doi:10.1016/S0021-9258(17)37525-7. 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. S2CID 8659319.
  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

PDB gallery
  • 1bhj: CRYSTAL STRUCTURE OF APO-GLYCINE N-METHYLTRANSFERASE (GNMT) 1bhj: CRYSTAL STRUCTURE OF APO-GLYCINE N-METHYLTRANSFERASE (GNMT)
  • 1d2c: METHYLTRANSFERASE 1d2c: METHYLTRANSFERASE
  • 1d2g: CRYSTAL STRUCTURE OF R175K MUTANT GLYCINE N-METHYLTRANSFERASE FROM RAT LIVER 1d2g: CRYSTAL STRUCTURE OF R175K MUTANT GLYCINE N-METHYLTRANSFERASE FROM RAT LIVER
  • 1d2h: CRYSTAL STRUCTURE OF R175K MUTANT GLYCINE N-METHYLTRANSFERASE COMPLEXED WITH S-ADENOSYLHOMOCYSTEINE 1d2h: CRYSTAL STRUCTURE OF R175K MUTANT GLYCINE N-METHYLTRANSFERASE COMPLEXED WITH S-ADENOSYLHOMOCYSTEINE
  • 1kia: Crystal structure of glycine N-methyltransferase complexed with S-adenosylmethionine and acetate 1kia: Crystal structure of glycine N-methyltransferase complexed with S-adenosylmethionine and acetate
  • 1nbh: Structure of glycine N-methyltransferase complexed with S-adenosylmethionine and acetate, GNMT:SAM:Ace 1nbh: Structure of glycine N-methyltransferase complexed with S-adenosylmethionine and acetate, GNMT:SAM:Ace
  • 1nbi: Structure of R175K mutated glycine N-methyltransferase complexed with S-adenosylmethionine, R175K:SAM. 1nbi: Structure of R175K mutated glycine N-methyltransferase complexed with S-adenosylmethionine, R175K:SAM.
  • 1r74: Crystal Structure of Human Glycine N-Methyltransferase 1r74: Crystal Structure of Human Glycine N-Methyltransferase
  • 1r8x: Crystal Structure of Mouse Glycine N-Methyltransferase (Tetragonal Form) 1r8x: Crystal Structure of Mouse Glycine N-Methyltransferase (Tetragonal Form)
  • 1r8y: Crystal Structure of Mouse Glycine N-Methyltransferase (Monoclinic Form) 1r8y: Crystal Structure of Mouse Glycine N-Methyltransferase (Monoclinic Form)
  • 1xva: METHYLTRANSFERASE 1xva: METHYLTRANSFERASE
  • 2azt: Crystal structure of H176N mutant of human Glycine N-Methyltransferase 2azt: Crystal structure of H176N mutant of human Glycine N-Methyltransferase
  • 2idj: Crystal Structure of Rat Glycine N-Methyltransferase Apoprotein, Monoclinic Form 2idj: Crystal Structure of Rat Glycine N-Methyltransferase Apoprotein, Monoclinic Form
  • 2idk: Crystal Structure of Rat Glycine N-Methyltransferase Complexed With Folate 2idk: Crystal Structure of Rat Glycine N-Methyltransferase Complexed With Folate
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