Nucleic acid metabolism, inhibition

The mechanism of inhibition of these protozoal infections by the most active drugs, puromycin and the aminonucleoside, is not known. Puromycin and nucleocidin both interfere with protein synthesis, but the aminonucleoside does not. It is known to be demethylated to 3 -amino-3-deoxyadenosine, which is phosphorylated and interferes with nucleic acid metabolism (see above). Whether puromycin must be converted to the aminonucleoside before it can inhibit protozoa has not been established. Some purine analogues known to interfere with nucleic acid metabolism, however, are less effective as antiprotozoal agents, even in vitro, perhaps because their effects are primarily on the de novo pathway which many, if not all, protozoa do not use [406]. 

The alkylating agents can transfer an alkyl radical to a suitable receptor site. Alkylation of DNA within the nucleus represent the major interactions which will lead to cell death. These agents react chemically with sulfhydryl, carboxyl, amino and phosphate groups of other cellular nucleophiles in the cells which make them unavailable for the normal metabolic reactions. Alkylating agents react with nucleic acid and inhibit... 

After metabolic activation, it depoly-merizes DNA and causes chromosomal damage and also nucleic acid synthesis inhibition. It is found to be effective in Hodgkin s disease and carcinoma of lungs. 

Studies of canavanine interaction with the tobacco hornworm and J-. miTior also revealed the marked ability of canavanine.to inhibit whole organism incorporation of [ Hjthymidine and uridine into trichloroacetic acid-precipitated materials. When canavanine is provided simultaneously with the appropriate radio-labeled precursor, ample evidence for curtailed nucleic acid metabolism emerges but protein synthesis is unaffected (Table I, exp. I). In experiment II, canavanine is allowed to assimilate... 

Nucleic acid metabolism is a feature that is common to all living things and few steps in the process in fungi are sufficiently different from those in other organisms to be used as an effective target for selective fungicides. Consequently, few compounds have been discovered that are not limited by their lack of specificity. In those fungicides known to inhibit nucleic acid biosynthesis the basis for the observed specificity is not understood. 

Several compounds may interfere with nucleic acid metabolism but commonly their effects are secondary to their primary mode of action, for example, the benzimidazoles. Compounds that inhibit nucleic acid biosynthesis directly are either phenylamides, pyrimidines or hydroxy-pyrimidines. Recently, the phenoxyquinolines were identified as exhibiting a novel mode of action in purine biosynthesis and are potentially useful fungicides. 

The dicarboximides inhibit spore germination and cause increased branching, swelling and lysis of germ tubes and hyphal tips. Effects on cell division have been reported but no major inhibition of nucleic acid metabolism, respiration, protein or lipid synthesis has been observed. 

An understanding of the biochemistry of peptidoglycan (PG murein) that comprises bacterial cell walls is very important medically since blockage of its synthesis was the first, and continues to be a primary, point of attack in the control of bacterial infection. In addition to inhibition of cell wall synthesis, antimicrobial drug s main mechanisms are interference with nucleic acid synthesis, inhibition of folate metabolism, and binding to ribosomes to disrupt protein synthesis (Table 16-2). 

Antibiotics that Inhibit Folic Acid Synthesis and Nucleic Acid Metabolism j... 

Examples of teratogenic compounds which interfere with nucleic acid metabolism are cytosine arabinoside, which inhibits DNA polymerase, mitomycin C, which causes cross-linking, and 6-... 

Thiouracil. 2,3-Dihydro-2-ihioxo-4(IH)-pyri-midinone 2-mercapto-4-hydroxypyrimidine 4-hydroxy -2( I ft) -pyrimidinethione 2 -mercapto -4( 1H) -py rimidinone 6 -hydroxy -2 -mercaptopyrimidine 2-mercapto-4. pyrimi -done Deracil. C4H4N,OS mol wt 128.15. C 37.49%, H 3.15%, O 12.48%, N 21.86%, S 25 02%. Occurs in seeds of Brassica, Cruciferae Purves, Brit. J. Exp. Pathol 22, 241 (1941). Prepd by condensing ethyl formylacetate with thiourea Wheeler. Liddle, 3m. Chem. J. 40, 550(1908). Antithyroid activity results from its interference with the iodina-tion of thyroxine precursors see Maloof, Soodak, Pharmacol. Rev. 15, 72-79 (1963). Inhibition of nucleic acid metabolism Cardeilhac, Proc, Soc. Exp. Biot Med. 125, 692 (1967). Toxicology K. K. Carroll, R. L, Noble, J. Pharmacol. Exp. Ther. 97, 478 (1949). 

Mechanism of action Pentamidine s mechanism of action is unknown but may involve inhibition of glycolysis or interference with nucleic acid metabolism of protozoans and fungi. Preferential accumulation of the drug by susceptible parasites may account for its selective toxicity. 

Leishmania, parasitic protozoa transmitted by flesh-eating flies, cause various diseases ranging from cutaneous or mucocutaneous lesions to splenic and hepatic enlargement with fever. Soilium stibogluconate (pentavalent antimony), the primary drug in all forms of the disease, appears to kill the parasite by inhibition of glycolysis or effects on nucleic acid metabolism. Alternative agents include pentamidine (for visceral leishmaniasis), metronidazole (for cutaneous lesions), and amphotericin B (for mucocutaneous leishmaniasis). 

Oxamniquine is activated via esterification to a biological ester that spontaneously dissociates to an electrophile, which alkylates the helminth DNA, leading to irreversible inhibition of nucleic acid metabolism (Fig. 39.20) (72). Resistant helminths do not esterify oxamniquine therefore, activation does not occur. Other metabolic reactions consist of oxidative reactions, leading to inactivation (Fig. 39.20). The metabolites are excreted primarily in the urine. 

Metal ions can also react with amino and sulfhydiyl groups of proteins involved in nucleic acid metabolism. This frequently results in an inhibition or dysfunction of the corresponding enzymes. By this metals can contribute in an indirect way to alterations in genetic information by affecting replication fidelity. Metal compounds can also cause DNA strand breaks indirectly, e.g., by causing depurination of DNA or via their involvement in generating oxygen free radicals. 

Conversion to the isopropylamine salt is carried out before it is used as a herbicide. Its mode of action appears to be interference with the biosynthesis of aromatic amino acids such as phenylalanine. This in turn inhibits nucleic acid metabolism and protein synthesis. 

In all studies carried out to date on enzymes of nucleic acid metabolism, MMPR-OP has shown specificity for lysine residues. Inhibition of other enzymes of nucleic acid metabolism by MMPR-OP can be taken as presumptive evidence for the presence of lysines in their active... 

While the studies of Boyland and Roller and Elion and co-workers, which were conducted in vivo, do suggest that urethane has a specificity for pyrimidine biosynthesis, Kaye could not demonstrate in vitro any significant inhibition by urethane of several enzymes involved in nucleic acid metabolism. Both urethane and its A -hydroxy metabolite bear a structural resemblance to carbamyl phosphate and carbamyl-L-aspartate. The enzyme aspartate transcarbamylase begins pyrimidine biosynthesis by catalyzing the formation of carbamyl-L-aspartate from carbamyl phosphate and l-aspartate. Giri and Bhide have reported that in vivo administration of urethane decreased aspartate transcarbamylase activity of lung tissue of adult male and (to a lesser extent) female mice no in vitro inhibition could be demonstrated. 

FIuazifop (2-[4-(5-trifluoromethyl-2-pyr1dyloxy)phenoxy]propionate) is a grass-specific herbicide. It is an aryloxyphenoxypropionate compound and these herbicides have been shown to kill sensitive species by causing necrosis of meristematic tissues. A number of studies on the mode of action of the aryloxyphenoxypropionates have only been able to demonstrate an inhibition of lipid metabolism. No detectable effects on CO2 fixation or carbohydrate, amino acid or nucleic acid metabolism have been shown ( Walker 1988a,). Cyclohexanedione herbicides, such as sethoxydim,... 

Inhibitors not primarily involving photosynthesis.—Of the herbicides which do not inhibit photosynthesis, the phenoxycarboxylic herbicides have received the most attention with respect to their influence on the soil algae. These herbicides act on higher plants through interfering with nucleic acid metabolism and disrupting translocation systems. 

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