Polymerase action characteristics

Intoxication by aflatoxkis is referred to as aflatoxicosis. Edema and necrosis of hepatic and renal tissues seem characteristic of aflatoxicosis, and hemorrhagic enteritis accompanied by nervous symptoms often appear ki experimental animals. The mode of action of aflatoxkis kivolve an kiteraction with DNA and inhibition of the polymerases responsible for DNA and RNA synthesis (96). 

All replication-competent retroviruses possess a characteristic enzyme, reverse transcriptase (RT), which is present at 20-70 mol/virus particle (1-3). The enzyme is cleaved, and thereby activated, from an inactive precursor by the action of another retroviral enzyme, the viral protease. All RTs possess three distinct enzymatic activities (1) an RNA-dependent DNA polymerase, which is the RT in the strict sense of the word, (2) an RNase H, and (3) a DNA-dependent DNA polymerase. After infection of a new host cell, these different activities serve in turn to synthesize a cDNA of the viral RNA, to degrade RNA from the cDNA-RNA heteroduplex, and to duplicate the cDNA strand (reviewed in ref. 4). 

An important characteristic of rifamycins is their mechanism of action. These were the first antibiotics found to selectively inhibit RNA synthesis by binding to the bacterial DNA dependent RNA polymerase (11,12). This aspect, besides being widely exploited for studies of molecular biology, suggested that these antibiotics were particularly suitable for chemical modification. 

Ansa-macrolides - Extensive progress in the study and clinical use of rifampin (rifampicin) and other rifamycins is reflected in the more than a hundred publications dealing with their antibacterial anti-viral (see Chapter 11). pharmacokinetic and therapeutic qualities . Characteristically, ansa-macrolides (ansa-mycinsZ J ). the rifamycins. streptovaricin. and tolypomycin. are thought to exert their antibacterial action through suppression of RNA-polymerase function,... 

It was found that the macrocyclic ring of rifamycin was responsible for the complex formation of the antibiotic with E. coli RNA polymerase and for the inhibitory effect of the antibiotic on the enzyme. Changes in other parts of the molecule have little effect on the direct action on E. coli RNA polymerase but may affect its permeability characteristics . Some derivatives of rifamycin, prepared by substitution with cyclic secondary amines, displayed activity against rifampicin resistant mutants of Staphylococcus aureus . ... 

Intercalation is involved in the mechanism of action of two other types of substances some antimalarial drugs and the anthracyoline antibiotics (Fig. 6). The complex they form with double-stranded DNA exhibits many characteristics of the acridine-DNA complex they modify in the same way the hydrodynamic properties of DNA. Chloroquine and quinacrine inhibit the in vitro activity of both DNA primed polymerases, and this is related with the block in nucleic acid synthesis observed when bacteria or plasmodia are treated with these drugs. 

The in vitro cytotoxicity of DMDC against L1210 cells was prevented dose depen-dently by 2 -deoxycytidine, suggesting that DMDC is phosphorylated by deoxycytidine kinase. Unlike ara-C, DMDC was not a substrate of cytidine deaminase from mouse kidney.33 Together with these characteristics, chemically synthesized DMDCTP was a potent inhibitor of DNA polymerase a, P, and y from calf thymus with Ki values of 0.42, 2.52, and 1.00 pM, respectively, in a manner competitive with dCTP, while ara-CTP inhibited only DNA polymerase a with a K of 1.10 pM.32 it was also found that DMDCTP was incorporated into DNA molecules at the site complementary to guanine by the action of DNA... 

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