Methylation of nucleic acids

Streptozocin (Zanosar), a water-soluble nitrosourea produced by the fungus Streptomyces achromogenes, acts through methylation of nucleic acids and proteins. In addition, it produces rapid and severe depletion of the pyridine nucleotides nicotinamide adenine dinucleotide (NAD) and its reduced form (NADH) in liver and pancreatic islets. 

Figure 7.5 Metabolism of dime-thylnitrosamine to the reactive car-bonium ion intermediate responsible for methylation of nucleic acids and thought to be the ultimate carcinogen.

Methylation of nucleic acids is considered further in Chapers 27 and 28. Methylation of carboxyl groups... 

The lipotropic agents are intimately involved with methylation and it is perhaps through this mechanism that they exert their effects. Aberrant methylation of nucleic acids and a relation to carcinogenesis under a variety of conditions, is currently under intensive investi-... 

The methylation cycle proceeds as follows. Methionine can be converted to S-adenosylmethionine (SAM). SAM is a universal methyl donor and is required in most or alJ methylation events occurring in the body. For example, SAM is used in the synthesis of creatine and carnitine and in the methylation of nucleic acids and proteins. With the donation of the methyl group, SAM is converted to S-ade-nosylhomocystcine (SAH), as shown in Figure 9-4. SAH is finally broken down to homocysteine, completing the methylation cycle. The point of departure of the 1-carbon unit, derived from serine, from the methylation cycle is indicated by the section symbol (g). 

Table 28 2 doesn t include all of the nucleoside components of nucleic acids The presence of methyl groups on pyrimidine and purine rings is a common and often important variation on the general theme... 

Dacarbazine is activated by photodecomposition (chemical breakdown caused by radiant energy) and by enzymatic N-demethylation. Formation of a methyl carbonium ion results in methylation of DNA and RNA and inhibition of nucleic acid and protein synthesis. Cells in all phases of the cell cycle are susceptible to dacarbazine. The drug is not appreciably protein bound, and it does not enter the central nervous system. 

Cieplak, P., Caldwell, J. W., Kollman, P. A., Molecular mechanical models for organic and biological systems going beyond the atom centered two body additive approximation aqueous solution free energies of methanol and IV-methyl acetamide, nucleic acid base, and amide hydrogen bonding and chloroform/water partition coefficients of the nucleic acid bases, J. Comput. Chem. 2001, 22, 1048-1057... 

Tipson devoted most of his years in Levene s laboratory accomplishing seminal work on the components of nucleic acids. To determine the ring forms of the ribose component of the ribonucleosides he applied Haworth s methylation technique and established the furanoid structure for the sugar in adenosine, guanosine, uridine, and thymidine. He showed that formation of a monotrityl ether is not a reliable proof for the presence of a primary alcohol group in a nucleoside, whereas a tosyl ester that is readily displaced by iodide affords clear evidence that the ester is at the 5-position of the pentofuranose. Acetonation of ribonucleosides was shown to give the 2, 3 -C -isopropyl-idene derivatives, which were to become extensively used in nucleoside and nucleotide chemistry, and were utilized by Tipson in the first chemical preparation of a ribonucleotide, inosinic acid. 

The bases that occur in nucleic acids are aromatic heterocyclic compounds derived from either pyrimidine or purine. Five of these bases are the main components of nucleic acids in all living creatures. The purine bases adenine (abbreviation Ade, not A ) and guanine (Gua) and the pyrimidine base cytosine (Cyt) are present in both RNA and DNA. In contrast, uracil (Ura) is only found in RNA. In DNA, uracil is replaced by thymine (Thy), the 5-methyl derivative of uracil. 5-methylcyto-sine also occurs in small amounts in the DNA of the higher animals. A large number of other modified bases occur in tRNA (see p. 82) and in other types of RNA. 

The similar accuracies of different well-parameterized continuum models implies that they will also perform similarly for the computation of partition coefficients, and that has proven to be the case in most studies to date (see, for example, Bordner, Cavasotto, and Abagyan 2002 and Curutchet et al. 2003b). In Table 11.4 the previously presented SMx results for the chloroform/water partitioning of die methylated canonical nucleic acid bases are compared to results from die MST-ST/HF/6-31G method, and also to purely electrostatic results obtained using a multipole expansion SCRF method. As the latter does not include any accounting for non-electrostatic effects, its performance is significantly degraded compared to the other two. 

Swann, PF. Magee, P.N. (1968) Nitrosamine-induced carcinogenesis. The alkylation of nucleic acids of the rat by A-methyl-A -nitrosourea, dimethylnitrosamine, dimethyl sulphate and methyl methanesulphonate. Biochem. J., 110, 39-47... 

Ekpenyong Kl, Shetlar MD (1979) Photochemical reactions of cytosine N-methyl analogs in alcoholic solutions. Photochem Photobiol 30 455-461 Elad D (1976) Photoproducts of purines. In Wang SY (ed) Photochemistry and photobiology of nucleic acids. Academic Press, New York, pp 357-380 Elad D, Rosenthal I (1969) Photochemical alkylation of caffeine with amino-acids. Chem Commun 905-906... 

Clark SJ, Harrison J, Paul CL, Frommer M. High sensitivity mapping of methylated cytosines. Nucleic Acids Res 1994 22 2990-2997. 

G.K. Forde et al., Comprehensive study of the effects of methylation on tautomeric equilibria of nucleic acid bases. J. Phys. Chem. B 110, 15564—15571 (2006)... 

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