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Analogues of Nucleic Acid Components: Mechanisms of Action by P. Roy-Burman Ph. D. (auth.), P. Roy-Burman Ph. D. (eds.)

By P. Roy-Burman Ph. D. (auth.), P. Roy-Burman Ph. D. (eds.)

The reason for the layout of structural analogues of a typical metabolite is that such compounds could intervene within the usage or functionality of the metabolite. A compound that's powerful during this recognize should be known as an antimetabolite. to achieve success in chemotherapy of bacterial, viral, or tumor progress, an antimetabolite may still adversely have an effect on a few very important metabolic reactions within the parasite or parasitic tissue with no heavily endangering the host tissue. If a metabolic means of the offending development isn't the same as that of the host, it's most likely that the metabolism or task of a compound, structurally relating to a metabolite inquisitive about that technique, can be varied in those cells. Such adjustments are worthy for devising powerful medicines with selective activities. Sulfanilamide, a structural analogue of para­ aminobenzoic acid, interferes with the usage of this metabolite within the synthesis of folic acid, a vital issue for development. micro organism synthesize their very own folic acid and are incapable of using exogenously on hand folic acid. even though, the placement is strictly contrary within the animal host. that's, animal tissues can't synthesize folic acid and are completely established upon exogenous resources. those ameliorations in metabolism make attainable using sulfanilamide as a selective inhibitor of progress. different antibacterial or antiparasitic medicinal drugs, comparable to penicillin (BURCHALL, FERONE and HITCHINGS, 1965) and inhibitors of dihydrofolate reductase (HITCHINGS and BURCHALL, 1965; HITCHINGS, 1964; BURCHALL and HITCHINGS, 1965) have analogous fascinating selective toxicity effects.

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Extra resources for Analogues of Nucleic Acid Components: Mechanisms of Action

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These workers, therefore, stressed that the most probable effect of ara-ATP in the ascites cells is a direct interaction with the DNA polymerase to produce an inactive enzyme. Similarly, FURTH and COHEN (1967) have shown that the nucleoside triphosphate analogue inhibits DNA synthesis catalyzed by DNA polymerase isolated from calf thymus or bovine lymphosarcoma. The reaction kinetics suggest a form of mixed inhibition between ara-ATP and dATP. 01 mllmole is incorporated with ara-ATP-3H as substrate.

It has been demonstrated that the inhibition of the conversion of adenine to its nucleotides by xyl-ATP in cell-free extracts of TA3 cells is the result of a decreased rate of PRPP formation form ATP and ribose 5-phosphate. 8 mM, xyl-ATP inhibited nucleotide formation by 42, 1 Xyl-AMP----;.. Xyl-ADP----;.. Xyl-ATP Xyl~A 1 Rib"" Xyl-hypoxanthine 5~pho,p"" I Histidine + ATP----t--:: PRL 'hh~d" D1P osp opyn me nucleotides Fig. 18. The major inhibitory site (indicated by ~) Punne nucleotides "d'me Pynml nucleotides of the active metabolite of xyl-A 66, and 85 0/0, while the nucleoside itself did not produce inhibitory effects even at a concentration of 2 mM (ELLIS and LEPAGE, 1965 a).

E E - - - - - - E ATP, dTTP (low) dATP, dTTP (high) dCMP + Cytidi:eu~~~tJJ':smidine nucleotides ---t--c> ~ U~P~ Uridine t dUD\--/-~~dUTP LLdUMP~ dTMPVDeox yI I thymidine dTTP dCTP dUMP dTMP dTTP Deoxyribonucleoside diphosphates Fig. 25. Feedback controls in pyrimidine metabolism. (Thin lines indicate the steps that are subject to such controls, ~ inhibition, [> stimulation; *, in bacterial systems) Pyrimidines 42 enzyme is more effectively inhibited by UTP and other uri dine derivatives, thymidine, and orotidylate than by cytidine derivatives.

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