DNA methyltransferases DNMTs

Bonsch, D., Lenz, B., Fiszer, R., Frieling, H., Kornhuber, J., and Bleich, S. (2006) Lowered DNA methyltransferase (DNMT-3b) mRNA expression is associated with genomic DNA hypermethylation in patients with chronic alcoholism. J. Neural Transm. 113, 1299-1304. 

In multicellular eukaryotes, DNA methylation is associated with transcriptional silencing [3]. In these organisms, DNA methylation has been observed exclusively on the C5 position of the cytosine ring and is frequently found in CpG-rich regions. This process is attributed to the action of DNA methyltransferases (DNMTs), which utilize the cofactor, S-adenosyl-L-methionine. Approximately half of all human genes have CpG islands in their promoter regions but these stretches of DNA are typically... 

Various epigenetic targets have been investigated in drug discovery approaches. So far only HDAC and DNA methyltransferase (DNMT) inhibitors are approved for the treatment of human cancer or are currently investigated in clinical studies [69]. The search for histone methyltransferase inhibitors is far less developed. 

FdCyd is an inhibitor of DNA methyltransferase (DNMT) currently in Phase... 

Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, Jones PA. The human DNA methyltransferases (DNMTs) 1, 3a and 3b coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res 1999 27 2291-2298. 

DNA methylation is accomplished by DNA methyltransferases (DNMTs), which catalyze the transfer of a methyl group from S-adcnosyl-meth ionine to the 5-position of cytosine in the CpG dinucleotide. DNA hypermethylation within the promoter region of tumor suppressor genes involved in cell proliferation and differentiation is a common phenomenon in numerous solid tumors.4-5... 

Histone deacetylases (HDACs), histone acetyltransferases (HMTs), histone demethylases (HDMTs), protein arginine methyltransterases (PRMTs), histone arginine demethylases (HADs), and DNA methyltransferases (DNMTs). 

Acetylenic functionalities, as in peyssonenynes A and B (57 and 58) from the red alga Peyssonnelia caulifera (Yanuca Island, Fiji), ° are rare for macroalgae, with only one previous report of lipid acetylenes, produced by the red alga Liagorafarinosa Both 57 and 58 showed similar activity in a DNA methyltransferase (DNMT-1) enzyme inhibition assay, with an IC5o=16 and 9pmoll respectively, but peyssopyrone (59), also from... 

Abnormal DNA methylation patterns are a hallmark of most cancers. Dietary factors may influence the methylation process in different ways. First, methyl groups available for the formation of 5-adenosytmethionine (SAM) may be supplied from dietary factors. Second, dietary factors may modify the utilization of methyl groups by processes including shifts in DNA methyltransferase (Dnmt) activity, A third mechanism may relate to DNA demethylation activity. Finally, the DNA methylation patterns may influence the response to a bioactive food component [32],... 

Robertson KD, Keyomarsi K, Gonzales Fa et al. Difiierential mRNA expression of the human DNA methyltransferase (DNMTs)l, 3a and 3b during the GO/Gl to S phase transition in normal and tumor cells. Nucleic Acids Res 2000 28 2108-2113. 

C-methylation reaction is the methylation of the C-5 position of cytosine in DNA. In this case, the carbon C-5 of cytosine cannot directly act as a nucleophile. The electron withdrawal by N-3 and the carbonyl, however, makes the C-5—C-6 double bond electron deficient and prone to attack by nucleophiles in a reaction that is similar to a Michael reaction. In DNA methyltransferases (DNMTs), this nucleophile is the thio-late from a Cys residue. The addition product is nucleophilic and reacts with SAM via an Si,j2-like mechanism to capture the methyl group. The resulting intermediate then eliminates the Cys of DNMT to give the methylated cytosine product (Figure 1.9). The methylation of C-5 of cytosine is an example of converting an electron-deficient methyl acceptor to a nucleophile for the methyl-transfer reaction by addition of an active site Cys thiolate. 

DNA-cytosine methylation is a well-documented epigenetic process in the context of carcinogenesis (Kim 2005). DNA methyltransferases (DNMTs) are the enzymes responsible for methyl group transfer from AdoMet to cytosine in CG sequences. Thus, folate metabolism on such epigenetic processes has an obvious impact and the folate-mediated single-carbon metabolism network is an important biological research topic which is fundamental to public health. 

Recently, psammaplins were reported as potent histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors (see Table X) (772). Eleven psammaplins (see Table X), isolated from the sponge Pseudoceratina purpurea, were tested in the histone deacetylase (HDAC) enzyme assay at concentrations ranging from 16 nM to 10 pM, and the data obtained were compared to that of two standards, trichostatin A 300) and trapoxin A 301). There were three psammaplin derivatives whose IC50 values were in a... 

Enzyme-Based Histone Deacetylase (HDAC) and DNA Methyltransferase (DNMT) Inhibition Data, and Cell-Based p21 Promoter Activity Data, for the Psammaplins (772). 

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