Inhibition of enzyme synthesis

Repression of enzymes, inhibition of enzyme synthesis by a product (or products) of the metabolic pathway in which the enzyme operates. A means of control on metabolism. 

Cataboirte repression Inhibition of enzyme synthesis by increased concentrations of certain metabolic products. Enzymes subject to Cr. are formed in reponse to metabolic events (utilization of new nutrients by catabolic enzymes, synthesis of secondary products in certain developmental phases of microorganisms). C. r. is probably present in all organisms, although the molecular mechanisms are diverse. Examples of C.r. are glucose repression of catabolic enzymes in . coU and the enzymes of secondary metabolism in microorganisms, e.g. those for the s thesis of penicillin, actinomycin and riboflavin. 

COLE, M.A. 1977. Lead inhibition of enzyme synthesis in soil. Applied and Environmental Microbiology, 33, 262-268. 

In such branched systems, different synthetic pathways require the delivery of a common intermediate by a certain enzyme (enzyme A in this example). It can happen that the organism already has a sufficient supply of substance Z. As we shall see later, feedback mechanisms ensure that no further supply of the common intermediate is delivered. That can be brought about by inhibition of enzyme synthesis or, also, by inhibition of enzyme activity. In our example such inhibition would block the further production of substances X and Y. For in these cases, too, the enzyme A stands at the beginning of their respective synthetic pathways. 

FIGURE 17.9 The lac operon of E. coli. (a) Organization of the lac operon showing bound RNA polymerase, (b) Inhibition of enzyme synthesis in the absence of lactose. 

Lipogenesis is regulated at the acetyl-CoA carboxylase step by allosteric modifiers, phosphorylation/de-phosphorylation, and induction and repression of enzyme synthesis. Citrate activates the enzyme, and long-chain acyl-CoA inhibits its activity. Insulin activates acetyl-CoA carboxylase whereas glucagon and epinephrine have opposite actions. 

Figure 7.2 Biochemical pathways for the synthesis and metabolism of dopamine. (—) indicates drug inhibition of enzyme activity...

This is not discussed in detail since mechanisms of resistance have been carefully reviewed (Ghannoum and Rice 1999). It was pointed out that resistance has not been associated with modification of the structure. For the 1,2,4-triazoles that have been widely used, their effect is due to inhibition of the synthesis of ergosterol that is the dominant component of fungal cell membranes. Resistance is generally associated with modification of the target enzymes, for example, the epoxidation of squalene (Terbinafine) or 14a-demethylase (Fluconazole). Resistance of Candida albicans to the azole antifungal agent fluconazole demonstrated, however, the simultaneous occurrence of several types of mechanism for resistance (Perea et al. 2001) ... 

In 1985, it was reported by Hsiang et al. [43] that the cytotoxic activity of 20-(S)-camptothecin (CPT III) was attributed to a novel mechanism of action involving the nuclear enzyme topo I, and this discovery of unique mechanism of action revived the interest in CPT and its analogues as anticancer agents. CPT stabilizes the covalent, reversible topo I-DNA complex leading to the inhibition of DNA synthesis in mammalian cells and interferes with the topo I breakage-reunion reaction [44]. Clinical trials and structure-activity relationships have demonstrated the requirement of the a-hydroxy group, the... 

The reported (14) mechanisms of action of allelochemlcals Include effects on root ultrastructure and subsequent Inhibition of Ion absorption and water uptake, effects on hormone-induced growth, alteration of membrane permeability, changes In lipid and organic acid metabolism, inhibition of protein synthesis and alteration of enzyme activity, and effects on stomatal opening and on photosynthesis. Reduced leaf water potential Is one result of treatment with ferulic and p-coumaric acids (15). Colton and Einhellig (16) found that aqueous extracts of velvetleaf (Abutllon theophrastl Medic.) Increased diffusive resistance In soybean fGlycine max. (L.) Merr.] leaves, probably as a result of stomatal closure. In addition, there was evidence of water stress and reduced quantities of chlorophyll In Inhibited plants. 

Iron appeared to reduce the effects of orally or subcutaneously administered lead on blood enzyme and liver catalase activity (Bota et al. 1982). Treatment of pregnant hamsters with iron- or calcium-deficient diets in conjunction with orally administered lead resulted in embryonic or fetal mortality and abnormalities (ranting, edema) in the litters, while treatment with complete diets and lead did not (Carpenter 1982). Inadequate levels of iron in association with increased body burdens of lead enhanced biochemical changes associated with lead intoxication (Waxman and Rabinowitz 1966). Ferrous iron was reported to protect against the inhibition of hemoglobin synthesis and cell metabolism by lead it has been speculated that iron competes with lead uptake by the cell (Waxman and Rabinowitz 1966). In... 

Showdomycin inhibits synthesis of nucleic acid. Thiols, such as cysteine and glutathione (among other compounds), reverse this inhibition, and it is considered that the interaction of the maleimide moiety with sulfhydryl groups within the cell or in the membrane may be responsible for the selective inhibition of enzymes by show-... 

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the NAD(P)H-dependent reduction of 5,10-methylenetetrahydrofolate (CH2-THF) to 5-methyltetrahydrofolate (CH3-THF). CH3-THF then serves as a methyl donor for the synthesis of methionine. The MTHFR proteins and genes from mammalian liver and E. coli have been characterized,12"15 and MTHFR genes have been identified in S. cerevisiae16 and other organisms. The MTHFR of E. coli (MetF) is a homotetramer of 33-kDa subunits that prefers NADH as reductant,12 whereas mammalian MTHFRs are homodimers of 77-kDa subunits that prefer NADPH and are allosterically inhibited by AdoMet.13,14 Mammalian MTHFRs have a two-domain structure the amino-terminal domain shows 30% sequence identity to E. coli MetF, and is catalytic the carboxyterminal domain has been implicated in AdoMet-mediated inhibition of enzyme activity.13,14... 

Binding of Hg2 + to DNA may cause degeneration and chromosomal breakage of spermatogenic cells [235]. Moreover, mercuric chloride gives a direct inhibition of sequence synthesis in murine spermatogonia cells and possibly an inhibition of essential spermatogenic enzymes [236]. 

Recently, it has been shown that cell-permeable cerantides dramatically inhibited the synthesis of the two major membrane phospholipids, PC and PE (Bladergroen et al, 1999b Allan, 2000). The inhibition of phospholipid synthesis was rapid, within 2 h, and resulted in massive apoptosis after 16-24 h. The mechanism by which short-chain cerantides exert their effect on phospholipid synthesis is possibly cell type dependent. In baby-hamster kidney (BHK) fibroblasts rc synthesis was reduced at the level of CT, the putative rate-determining enzyme in the CDP-choline pathway (Allan, 2000). This conclusion was based solely on radio-label studies in combination with an earlier published observation (Wieder et al, 1995) showing that C2-SM (the SM generated from C2-ceramide by SM synthase, which was actively synthesized in the BHK-cells) inhibited CT activity in vitro. On the other hand, data obtained from studies with rat-2 fibroblasts clearly showed that short-chain cerantides regulate the synthesis of PC and PE mainly at the final step of the CDP-pathways. This conclusion was based on the following observations (a) incorporation of [ H]-choline into PC and... 

The most convincing example that inhibition of PC synthesis can induce apoptosis comes from a cell line with a temperature-sensitive defect in one of the enzymes in the CDP-choline pathway (Cui et al, 1996). The MT58 cell line is a Chinese hamster ovary (CHO) derived cell line with a mutation in CTP phosphocholine cytidylyltransferase (CT), which renders the... 

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