have two Mat genes: Mat1a is mostly expressed in the liver, Mat2a has a broad expression pattern and its activity is regulated by Mat2b. AdoMet is the major methyl donor whose accepting nucleophiles are carbon, nitrogen, oxygen or sulfur atoms on proteins, nucleic acids, carbohydrates, lipids and small molecules in the reaction catalyzed by methyltransferases (MTs). Methylation/demethylation modifications, like phosphorylation/dephosphorylation, exert important regulatory roles. There are over 200 known or predicted MTs; the AdoMet-MT reactions play important roles in transcription, translation and epigenetics, protein localization and signaling. The byproduct of MT-catalyzed reactions is S-adenosylhomocysteine (SAH), itself a potent inhibitor of the transmethylation reaction. SAH is reversibly hydrolyzed to homocysteine (Hcy) and adenosine by Ahcy. Under equilibrium conditions the production of SAH is favored; however, rapid removal of Hcy and adenosine products, prompt the reaction towards Hcy. The metabolism of Hcy lies at the cross-roads of several pathways. Hcy can be methylated to methionine via the cobalamin-dependent and -independent pathways. The first is the predominant reaction in most tissues and is carried out by methionine synthase (Mtr). In the course of the reaction, the cobalamin (Cbl) co-factor can get oxidized which renders the enzyme inactive; reductive methylation carried out by Mtrr restores the functional enzyme. The requirement for the 1 carbon (1C) donor 5-methyl tetrahydrofolate and the generation of tetrahydrofolate (THF) in the reaction, engages folate metabolism whose components are the folate cycle and the folate mediated one-carbon metabolic pathways. The cobalamin-independent, betaine-dependent pathway is the major route of Hcy remethylation in the liver. The choline derived betaine is the methyl donor in the reaction catalyzed by the zinc metalloprotein Bhmt with dimethylglycine (DMG) as a by-product. DMG exerts strong feedback inhibition upon Bhmt activity. DMG and sarcosine, the monomethyl glycine derived from the AdoMet-dependent reaction catalyzed by Gnmt, are 1C donors for the production of active folates in mitochondria. Interestingly, Gnmt can interact with 4S polycyclic aromatic hydrocarbons (PAH) which are potential carcinogens; the possible role of Gnmt in cellular detoxification and thus the presence of a second and distinct function, renders it a candidate moonlight protein. The other route of Hcy metabolism is the transsulfuration pathway which results in the production of cysteine and other metabolites downstream of it. AdoMet inhibits the folate-dependent Hcy methylation and activates the first enzyme in the transsulfuration pathway. This way, Hcy metabolism is channeled to remethylation when methionine/AdoMet levels are low, whereas when methionine/AdoMet levels are high, it is channeled to transsulfuration. The remethylation pathways converge on the methionine cycle and lead to homocysteine production; the transsulfuration pathway irreversibly degrades Hcy. The methionine cycle can also follow the salvage pathway with AdoMet in this case leading to the synthesis of polyamines. AdoMet is first decarboxylated (dc) by Amd1; dcAdoMet, also known as S-adenosylmethioninamine along with the polyamine putrescine derived from ornithine, is used in the consecutive synthesis of spermidine and spermine, respectively. A byproduct of polyamine synthesis is methylthioadenosine (MTA) whose catabolism, in the first of a series of steps in the salvage pathway, involves methylthioadenosine phosphorylase (Mtap). Mtap is deleted in several types of cancer; frequently, it is co-deleted with the Cdkn2a tumor suppressor gene, also known as p16. Available data suggests that Mtap may act as a tumor suppressor. The first steps of the salvage pathway have been rather extensively studied; however, the rest of the reactions and the enzymes that perform them are not well characterized in mammalian cells. AdoMet also mediates radical reactions that promote co-factor and natural product biosynthesis in anaerobically grown organisms. AdoMet radical enzymes represent a very large superfamily. The pathways of methionine, homocysteine and folate metabolism are intimately interconnected. Defects in enzymes within these pathways have been associated with several disorders and conditions. In addition, impairments of MT transmethylation reactions have been associated with cancer. To see the ontology report for Gviewer, annotations and download, click here ...(less)