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- W2034602099 abstract "In recent years 5methylcytosine residues in DNA have been implicated to have an important role in the control of eucaryotic gene expression (see Razin and Riggs, Science 210,604-610,198O). Consequently, there has been much interest in cytosine analogs such as 5azacytosine (5.azaC) and 5-fluorocytosine (5.fluoro-C), which, when incorporated into DNA, inhibit methylation and profoundly affect gene expression and differentiation (see Taylor and Jones, JMB 162, 679-692, 1982). The degree of hypomethylation far exceeds the levels of such analogs in DNA and is not simply a result of their inability to serve as methyl acceptors It is now clear that DNAs containing low levels of these analogs are potent inhibitors of DNA-cytosine methyltransferase (DCMT), but the mechanism of inhibition is unresolved. In this report, we review pertinent literature and formulate a proposal for the molecular mechanism by which DCMT is inhibited by DNA containing 5-aza-C or 5fluoroC. A similar mechanism explains how small amounts of 5-aza-C or 5-fluoro-C in tRNA cause specific loss of tRNA-cytosine methyltransferase activity (Lu et al., Biochem. Pharmacol. 28, 489-495, 1979; Lu and Randerath, Cancer Res. 40, 2701-2705, 1980). A General Mechanism for Enzymes That Catalyze Electrophilic Substitution at the 5 Position of Pyrimidines, and Properties of Inhibitory Analogs Numerous chemical and enzymic studies have revealed that enzymes which catalyze electrophilic substitution reactions at the 5 position of the pyrimidine heterocycle proceed by the general mechanism shown below (Starzyk et al., Nature 298, 136-140, 1982; Pogolotti and Santi, Bioorgan. Chem. 1, 277-31 I, 1977). In this mechanism, a nucleophilic catalyst of the enzyme adds to the 6 position of the heterocycle to produce a negative charge at the 5 position and activates what is otherwise an inert carbon for reaction with an electrophile (R+). Subsequent abstraction of the proton at carbon-5 of intermediate 3 and /3elimination provide the product and the active enzyme. Enzymes proceeding by this mechanism include dTMP synthase, dUMP hydroxymethylase, and dCMP hydroxy-" @default.
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- W2034602099 date "1983-05-01" @default.
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- W2034602099 title "On the mechanism of inhibition of DNA-cytosine methyltransferases by cytosine analogs" @default.
- W2034602099 doi "https://doi.org/10.1016/0092-8674(83)90327-6" @default.
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