The One-Carbon Units include different groups linked to THF:
Details of folate Pathways
They are produced during the metabolism of some Aminoacids, namely:
- Serine
- Histidine (via N-formimidoyl-L-glutamate)
THF acts as a carrier of reactive single carbon units, which are bonded to N-5 and N-10.
Either serine or glycine can act as methylene donor, giving N5,N10-methyleneTHF. This behaves as "virtual formaldehyde" H2C=O in reactions.
The oxidation level can be changed to methyl or methenyl by reduction or oxidation; methenylTHF can be hydrolyzed to formylTHF.
These derivatives can be used in synthetic reactions as donors of single C at the appropriate oxidation level. This may be a more important role for glycine metabolism than potential delivery of single C to catabolic reactions.
SAME synthesis
Two genes (MAT1A and MAT2A) encode for the essential enzyme methionine adenosyltransferase (MAT), which catalyzes the biosynthesis of S-adenosylmethionine (SAMe) , the principal methyl donor and, in the liver, a precursor of glutathione.
Kegg Pathway
- MAT1A is expressed mostly in the liver
- MAT2A is widely distributed. MAT2A is induced in the liver during periods of rapid growth and dedifferentiation. MAT2A activity
In human hepatocellular carcinoma (HCC) MAT1A is replaced by MAT2A. This is important pathogenetically because MAT2A expression is associated with lower SAMe levels and faster growth, whereas exogenous SAMe treatment inhibits growth.
Methionine adenosyltransferase
Regulation by hypoxia of methionine adenosyltransferase activity and gene expression in rat hepatocytes. 1998
Oxygen supply to the hepatic parenchyma is compromised by long- or short-term ethanol consumption and pathological conditions such as cirrhosis. Impairment in the production of S-adenosyl-L-methionine, the major methylating agent, occurs during hypoxia. In this study, the molecular mechanisms implicated in the regulation of S-adenosyl-L-methionine synthesis by oxygen levels were investigated
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h3. Methylation
Methylation targets are:
- DNA
- RNA
- Proteins
- Lipids
- Hormones and neurotransmitters
Methyl Donor
DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular process. These include, embryonic development, transcription, chromatine structure, X chromosome inactivation, genomic imprinting and chromosome stability. (Robertson 2005 Nat. Rev.)
Methylation contributing to epigenetic inheritance can occur either through DNA methylation or protein methylation
DNA methylation in vertebrates typically occurs at CpG sites (cytosine-phosphate-guanine sites; that is, where a cytosine is directly followed by a guanine in the DNA sequence); this methylation results in the conversion of the cytosine to 5-methylcytosine. The formation of Me-CpG is catalyzed by the enzyme DNA methyltransferase. The bulk of mammalian DNA has about 40% of CpG sites methylated but there are certain areas, know as CpG islands which are GC rich (made up of about 65% CG residues) where none are methylated. These are associated with the promoters of 56% of mammalian genes, including all ubiquitously expressed genes. 1-2% of the human genome are CpG clusters and there is an inverse relationship between CpG methylation and transcriptional activity.
DNA methylation
Protein methylation typically takes place on arginine or lysine amino acid residues in the protein sequence. Arginine can be methylated once (monomethylated arginine) or twice, with either both methyl groups on one terminal nitrogen (asymmetric dimethylated arginine) or one on both nitrogens (symmetric dimethylated arginine) by peptidylarginine methyltransferases (PRMTs). Lysine can be methylated once, twice or three times by lysine methyltransferases. Protein methylation has been most well studied in the histones. The transfer of methyl groups from S-adenosyl methionine to histones is catalyzed by enzymes known as histone methyltransferases. Histones which are methylated on certain residues can act epigenetically to repress or activate gene expression. Protein methylation is one type of post-translational modification.
Asimmetric dimethyl arginine
Regulation by Diet
Methyl Cycle Genomics
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