GNMT

This article is about the enzyme. For the machine translation system, see GNMT (translation).

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

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	OMIM: 606628; MGI: 1202304; HomoloGene: 7741; GeneCards: GNMT; OMA:GNMT - orthologs
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6p21.1 Start 42,960,754 bp[1] End 42,963,880 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17 22.9 cM|17 C Start 47,036,590 bp[2] End 47,040,094 bp[2]
RNA expression pattern Bgee Human Mouse (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 methyltransferase activity transferase activity folic acid binding protein binding glycine binding glycine N-methyltransferase activity identical protein binding S-adenosyl-L-methionine binding Cellular component cytoplasm cytosol Biological process glycogen metabolic process regulation of gluconeogenesis methionine metabolic process methylation S-adenosylmethionine metabolic process one-carbon metabolic process protein homotetramerization cellular nitrogen compound metabolic process S-adenosylhomocysteine metabolic process sarcosine metabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 17: 47.04 – 47.04 Mb PubMed search [3] [4]
Wikidata
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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]