Selective enzyme inhibition

Poor enzyme-selective inhibition between mammals and plant, with unfavorable mammal... 

The action mechanism of herbicidal activity of the alkylphosphonates lo was explored on the basis of biochemical experiments. Representative alkylphosphonates lo were selected to examine their inhibition against plant PDHc in vitro including enzyme activity assays, kinetic experiments, and enzyme selective inhibition. Correlation between the inhibitory potency against plant PDHc and the herbicidal activity of the alkylphosphonates lo was summarized on the basis of bioassay. 

As stated in Sects. 1.3.3 and 1.4.2 in Chap. 1, sodium salts of acetyl(methyl) phosphinic acid 1-2 and 1-3 could exhibit powerful inhibition against PDHc El in plant (pea) and bacteria E. coli). However, 1-2 and 1-3 had poor enzyme-selective inhibition between mammals and plant or bacteria, because they were also powerful inhibitors against human PDHc El [36]. 

Clacyfos exhibited an obvious advantage over those acylphosphinates or acy-Iphosphonates in enzyme-selective inhibition, crop safely, and effectiveness. It seems to be the first compound which shows practical herbicidal activity as a plant PDHc inhibitor. These results proved the rationality and effectiveness of our study on the biorational design of plant PDHc El inhibitor. 

Modulation of second-messenger pathways is also an attractive target upon which to base novel antidepressants. Rolipram [61413-54-5] an antidepressant in the preregistration phase, enhances the effects of noradrenaline though selective inhibition of central phosphodiesterase, an enzyme which degrades cycHc adenosiae monophosphate (cAMP). Modulation of the phosphatidyl iaositol second-messenger system coupled to, for example, 5-HT,, 5-HT,3, or 5-HT2( receptors might also lead to novel antidepressants, as well as to alternatives to lithium for treatment of mania. Novel compounds such as inhibitors of A-adenosyl-methionine or central catechol-0-methyltransferase also warrant attention. 

The second type of antifolates bind preferentially with, and thus selectively inhibit, the enzyme dihydrofolate reductase contained in the plasmodia. This interferes with the abiUty of the malaria parasites to convert dihydrofolate to tetrahydrofoUc acid. In the erythrocyte host, however, dihydrofolate... 

MAO is known to occur in at least two forms, MAO A and MAO B, based on substrate selectivity, inhibition by various dmgs, and cloning experiments. Clorgyline [17780-72-2] is a specific inhibitor of MAO A, which displays a substrate specificity for NE and serotonin. Deprenyl [2323-36-6] is a selective inhibitor of MAO B, and displays a substrate preference for P-phenylethylamine and benzyl amine. Dopamine and tyramine are substrates for both enzymes. 

This insertion is accomplished by an enzyme called transpeptidase. -Lactam antibiotics function as substrates for the transpeptidase, thereby establishing selective inhibition of bacterial cell wall synthesis. The structural similarity between -lactam antibiotics and the alanylalanine unit is remarkable as can be seen in Figure 6.8. 

Earlier we indicated that an alternative strategy to prevent ring cleavage is to use selective inhibition of the enzymes which catabolise the ring structure. 

II cleaves the two complementary strands of DNA four base pairs apart and the resulting 5 -phosphoryl groups become covalently linked to a pair of tyrosine groups, one in each half of the dimeric topoisomerase II enzyme. Several groups of drugs are known that selectively inhibit topoisomerases in bacteria (quino-lones) or mammalian cells (etoposide, tenoposide). Quinolones are used to treat bacterial infections inhibitors of mammalian topoisomerases are cytostatic drugs used for the treatment of cancer. 

Substances that do not target the active site but display inhibition by allosteric mechanisms are associated with a lower risk of unwanted interference with related cellular enzymes. Allosteric inhibition of the viral polymerase is employed in the case of HIV-1 nonnucleosidic RT inhibitors (NNRTl, see chapter by Zimmermann et al., this volume) bind outside the RT active site and act by blocking a conformational change of the enzyme essential for catalysis. A potential disadvantage of targeting regions distant from the active site is that these may be subject to a lower selective pressure for sequence conservation than the active site itself, which can lower the threshold for escape of the virus by mutation. 

Scofano et al. [375] observed that at low reagent to protein ratios (lOnmole/mg protein), DCCD selectively inhibited the phosphorylation of the enzyme by Pi and the... 

Although a few mechanisms have so far been proposed to explain the antimicrobial properties exhibited by proanthocyanidins (e.g., inhibition of extracellular enzymes) [86], Jones et al. [83] postulated that their ability to bind bacterial cell coat polymers and their abihty to inhibit cell-associated proteolysis might be considered responsible for the observed activity (Table 1). Accordingly, despite the formation of complexes with cell coat polymers, proanthocyanidins penetrated to the cell wall in sufficient concentration to react with one or more ultra-structural components and to selectively inhibit cell wall synthesis. Decreased proteolysis in these strains may also reflect a reduction of the export of proteases from the cell in the presence of proanthocyanidins [83]. 

The presence of an organic phase in the bioreaction medium is only useful when the partition coefficient of at least one reactant is significantly greater than the unity. The characteristics of the selected solvent clearly influence the partition coefficients of substrates and products between the two phases. When enzyme is inhibited by high substrate or product concentrations, it is convenient to use solvents with high partition coefficients while the opposite has to be done when enzyme has low affinity with its substrate. Eggers et al. [29] define the overall biphasic concentration referred to the total volume of the system ... 

Sildenafil (Viagra ), tadalafil (Cialis ), and vardenafil (Levitra ) act by selectively inhibiting phosphodiesterase (PDE) type 5, an enzyme that breaks down cGMP. By inhibiting the breakdown of cGMP, smooth muscle relaxation is... 

Elucidation of the activities of individual COX isoforms led to the development of drugs that selectively inhibit the inducible form of the enzyme, COX-2. Thus COX-2 inhibitors were expected to minimize NSAID gastrointestinal toxicity and antiplatelet effects (see Fig. 55-3).19 A common misconception is that COX-2 inhibitors are more effective than nonselective NSAIDs in relieving pain and inflammation. In clinical trials, patients experienced similar levels of pain relief with COX-2 inhibitors and nonselective NSAIDs. 

Enyzme catalysis is thus essential for all life. Hence the selective inhibition of critical enzymes of infectious organisms (e.g., viruses, bacteria, and multicellular parasites) is an attractive means of chemotherapeutic intervention for infectious diseases. This strategy is well represented in modem medicine, with a significant portion of antiviral, antibiotic, and antiparasitic drugs in clinical use today deriving their therapeutic efficacy through selective enzyme inhibition (see Table 1.1 for some examples). 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

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