GNMT

GNMT
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1R74, 2AZT
Identifiers
Aliases	GNMT, HEL-S-182mP, glycine N-methyltransferase
External IDs	MGI: 1202304 HomoloGene: 7741 GeneCards: GNMT
Gene ontology Molecular function • methyltransferase activity • transferase activity • folic acid binding • protein binding • glycine binding • glycine N-methyltransferase activity Cellular component • cytoplasm • cytosol Biological process • glycogen metabolic process • regulation of gluconeogenesis • methionine metabolic process • methylation • S-adenosylmethionine metabolic process • cellular protein modification process • one-carbon metabolic process • protein homotetramerization • glyoxylate metabolic process Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	27232	14711
Ensembl	ENSG00000124713	ENSMUSG00000002769
UniProt	Q14749	Q9QXF8
RefSeq (mRNA)	NM_018960 NM_001318865	NM_010321
RefSeq (protein)	NP_061833.1 NP_001305794.1	NP_034451.1
Location (UCSC)	Chr 6: 42.96 – 42.96 Mb	Chr 17: 46.73 – 46.73 Mb
PubMed search	[1]	[2]
Wikidata

Glycine N-methyltransferase is an enzyme that in humans is encoded by the GNMT gene.^[3][4][5]

Discovery

The enzyme was first described by Blumenstein and Williams (1960) in guinea pig liver.^[6] However, this enzyme was not purified until 1972 in the rabbit liver by Kerr.^[7] In 1984, Cook and Wagner demonstrated that a liver cytosolic folate binding protein is identical to GNMT.^[8] The human GMNT gene was cloned in 2000 by Chen and coworkers.^[4]

Tissue distribution

GNMT is an abundant enzyme in liver cytosol and consists of 0.9% to 3% of the soluble protein present in liver.^[9] In addition to liver, GNMT activity has been found in a number of other tissues including pancreas and kidney.^[7] GNMT is most abundant in the peri-portal region of the liver and exocrine tissue of the pancreas.^[9] The GNMT proteins located in tissues that are actively in secretion, such as the proximal kidney tubules, the submaxillary glands and the intestinal mucosa.^[9] GNMT is also expressed in various neurons presented in the cerebral cortex, hippocampus, substantia nigra and cerebellum.^[10] 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.^{[9][11][12][13][14]} 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.^[13] The structure of recombinant rat, mouse and human GNMTs have been solved.^[15][16] 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)^[17] and participates in the detoxification pathway in liver cells.^[5] 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.^[7] GNMT regulates the relative levels of SAM and SAH. Since SAM is the methyl donor for almost all cellular methylation reactions.^[17] GNMT is therefore likely to regulate cellular methylation capacity.^[17][18] An endogenous ligand of GNMT, 5-methyltetrahydropteroylpentaglutamate (5-CH3-H4PteGIu5) is a powerful inhibitor of this enzyme.^[19] 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.^[17][19]

In addition to the methyltransferase activity, the 4S polycyclic aromatic hydrocarbon (PAH)-binding protein and GNMT are one and the same protein.^[20] The catalytic site resembles a molecular basket, unlike most other SAM-dependent methyltransferases,^[15] 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.^[21]

Clinical significance

GNMT has been shown to detoxify some environmental carcinogens such as polyaromatic hydrocarbons and aflatoxin.^[22]

There is mounting evidence that supports the involvement of GNMT deficiency in liver carcinogenesis.^[23]

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.^[24]

References

Further reading

PDB gallery
1bhj: CRYSTAL STRUCTURE OF APO-GLYCINE N-METHYLTRANSFERASE (GNMT)  1d2c: METHYLTRANSFERASE  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  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  1nbi: Structure of R175K mutated glycine N-methyltransferase complexed with S-adenosylmethionine, R175K:SAM.  1r74: Crystal Structure of Human Glycine N-Methyltransferase  1r8x: Crystal Structure of Mouse Glycine N-Methyltransferase (Tetragonal Form)  1r8y: Crystal Structure of Mouse Glycine N-Methyltransferase (Monoclinic Form)  1xva: METHYLTRANSFERASE  2azt: Crystal structure of H176N mutant of human Glycine N-Methyltransferase  2idj: Crystal Structure of Rat Glycine N-Methyltransferase Apoprotein, Monoclinic Form  2idk: Crystal Structure of Rat Glycine N-Methyltransferase Complexed With Folate