| GNMT | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | GNMT , HEL-S-182mP, glycine N-methyltransferase | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 606628 MGI: 1202304 HomoloGene: 7741 GeneCards: GNMT | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Glycine N-methyltransferase is an enzyme that in humans is encoded by the GNMT gene. [5] [6] [7]
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]
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.
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.
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]
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]
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]
Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. Two major types of histone methyltranferases exist, lysine-specific and arginine-specific. In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group.
The genomic DNA of eukaryotes associates with histones to form chromatin. The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. Histone methylation is a principal epigenetic modification of chromatin that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis.
Sarcosine, also known as N-methylglycine, or monomethylglycine, is a amino acid with the formula CH3N(H)CH2CO2H. It exists at neutral pH as the zwitterion CH3N+(H)2CH2CO2−, which can be obtained as a white, water-soluble powder. Like some amino acids, sarcosine converts to a cation at low pH and an anion at high pH, with the respective formulas CH3N+(H)2CH2CO2H and CH3N(H)CH2CO2−. Sarcosine is a close relative of glycine, with a secondary amine in place of the primary amine.
Methionine synthase (MS, MeSe, MTR) is responsible for the regeneration of methionine from homocysteine. In humans it is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase). Methionine synthase forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle, and is the enzyme responsible for linking the cycle to one-carbon metabolism via the folate cycle. There are two primary forms of this enzyme, the Vitamin B12 (cobalamin)-dependent (MetH) and independent (MetE) forms, although minimal core methionine synthases that do not fit cleanly into either category have also been described in some anaerobic bacteria. The two dominant forms of the enzymes appear to be evolutionary independent and rely on considerably different chemical mechanisms. Mammals and other higher eukaryotes express only the cobalamin-dependent form. In contrast, the distribution of the two forms in Archaeplastida (plants and algae) is more complex. Plants exclusively possess the cobalamin-independent form, while algae have either one of the two, depending on species. Many different microorganisms express both the cobalamin-dependent and cobalamin-independent forms.
CYP27A1 is a gene encoding a cytochrome P450 oxidase, and is commonly known as sterol 27-hydroxylase. This enzyme is located in many different tissues where it is found within the mitochondria. It is most prominently involved in the biosynthesis of bile acids.
Phenylethanolamine N-methyltransferase (PNMT) is an enzyme found primarily in the adrenal medulla that converts norepinephrine (noradrenaline) to epinephrine (adrenaline). It is also expressed in small groups of neurons in the human brain and in selected populations of cardiomyocytes.
In enzymology, sarcosine dehydrogenase (EC 1.5.8.3) is a mitochondrial enzyme that catalyzes the chemical reaction N-demethylation of sarcosine to give glycine. This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-NH group of donor with other acceptors. The systematic name of this enzyme class is sarcosine:acceptor oxidoreductase (demethylating). Other names in common use include sarcosine N-demethylase, monomethylglycine dehydrogenase, and sarcosine:(acceptor) oxidoreductase (demethylating). Sarcosine dehydrogenase is closely related to dimethylglycine dehydrogenase, which catalyzes the demethylation reaction of dimethylglycine to sarcosine. Both sarcosine dehydrogenase and dimethylglycine dehydrogenase use FAD as a cofactor. Sarcosine dehydrogenase is linked by electron-transferring flavoprotein (ETF) to the respiratory redox chain. The general chemical reaction catalyzed by sarcosine dehydrogenase is:
In enzymology, a glycine N-methyltransferase is an enzyme that catalyzes the chemical reaction
Guanidinoacetate N-methyltransferase is an enzyme that catalyzes the chemical reaction and is encoded by gene GAMT located on chromosome 19p13.3.
Phosphatidylethanolamine N-methyltransferase is a transferase enzyme which converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC) in the liver. In humans it is encoded by the PEMT gene within the Smith–Magenis syndrome region on chromosome 17.
Protein arginine N-methyltransferase 1 is an enzyme that in humans is encoded by the PRMT1 gene. The HRMT1L2 gene encodes a protein arginine methyltransferase that functions as a histone methyltransferase specific for histone H4.
Histone-lysine N-methyltransferase 2A, also known as acute lymphoblastic leukemia 1 (ALL-1), myeloid/lymphoid or mixed-lineage leukemia1 (MLL1), or zinc finger protein HRX (HRX), is an enzyme that in humans is encoded by the KMT2A gene.
NEDD8-activating enzyme E1 regulatory subunit is a protein that in humans is encoded by the NAE1 gene.
Lysine N-methyltransferase 2C (KMT2C) also known as myeloid/lymphoid or mixed-lineage leukemia protein 3 (MLL3) is an enzyme that in humans is encoded by the KMT2C gene.
Inhibitor of growth protein 4 is a protein that in humans is encoded by the ING4 gene.
UMP-CMP kinase is an enzyme that in humans is encoded by the CMPK1 gene.
Collapsin response mediator protein 1, encoded by the CRMP1 gene, is a human protein of the CRMP family.
Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase. It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A, KMT2B, KMT2C, KMT2F, and KMT2G.
Polypeptide N-acetylgalactosaminyltransferase 14 is an enzyme that in humans is encoded by the GALNT14 gene.
Aldehyde dehydrogenase 1 family, member A1, also known as ALDH1A1 or retinaldehyde dehydrogenase 1 (RALDH1), is an enzyme that is encoded by the ALDH1A1 gene.
SET domain containing 1B is a protein that in humans is encoded by the SETD1B gene.
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