Inhibitors, of enzymes

The biochemical basis of penicillin action continues to be an area of active investigation. Penicillins are highly specific inhibitors of enzyme(s) involved in the synthesis of the bacterial cell wall, a structure not present in mammalian cells. Three principal factors are thought to be important for effective antibacterial action by a penicillin ... 

FIGURE 18.12 The use of inhibitors to reveal the sequence of reactions in a metabolic pathway, (a) Control Under normal conditions, the steady-state concentrations of a series of intermediates will be determined by the relative activities of the enzymes in the pathway, (b) Plus inhibitor In the presence of an inhibitor (in this case, an inhibitor of enzyme 4), intermediates upstream of the metabolic block (B, C, and D) accumulate, revealing themselves as intermediates in the pathway. The concentration of intermediates lying downstream (E and F) will fall. 

Inhibitors of enzyme causing buildup of acetylcholine in synapses... 

Table 47-12. Three inhibitors of enzymes involved in the glycosylation of glycoproteins and their sites of action.

We succeeded in showing that recycling of the enzyme was indeed possible in our IL solvent system, though the reaction rate gradually dropped with repetition of the reaction process. Since vinyl acetate was used as acyl donor, acetaldehyde was produced hy the hpase-catalyzed transesterification. It is well known that acetaldehyde acts as an inhibitor of enzymes because it forms a Schiff base with amino residue in the enzyme. However, due to the very volatile nature of acetaldehyde, it easily escapes from the reaction mixture and therefore has no inhibitory action on the lipase. However, this drop in reactivity was assumed to be caused by the inhibitory action of acetaldehyde oligomer which had accumulated in the [bmim][PFg] solvent system. In fact, it was confirmed that the reaction was inhibited by addition of acetaldehyde trimer. =... 

The presence of some substances may hinder the action of an enzyme. Such substances are known as inhibitors, and in some cases the inhibitor may be a metal. It is not necessary to describe all the ways in which an inhibitor may reduce the activity of an enzyme, but one way is by binding to the substrate. This is known as competitive inhibition, and it applies to cases in which the inhibitor competes with the substrate in binding to the enzyme. In noncompetitive inhibition, the inhibitor binds to the enzyme and alters its structure so it can no longer bind to the substrate. In some instances, certain metal ions function as inhibitors of enzyme action, which can be a cause of the toxicity referred to earlier. 

Substrates and inhibitors of enzymes that are involved in nucleotide and nucleoside metabolism... 

FIGURE 52-6 Biosynthesis/metabolism of steroids in the CNS. The conversion of delta5P to dehydroepiandrosterone (DHA) is postulated but not demonstrated. D5P and DHA inhibit and 3oc,5oc-THP potentiates GABAa receptor function, as summarized in Figure 52-7. Solid arrows indicate demonstrated pathways dotted arrows indicate possible pathways. Metabolic inhibitors of enzymes are indicated by . (Redrawn from [12], with permission.)... 

Bestatin (ubenimex) is a potent inhibitor of aminopeptidase N and aminopeptidase B,89 which was isolated from a culture filtrate of Streptomyces olivoreticuli during the search for specific inhibitors of enzymes present on the membrane of eukaryotic cells.90 Inhibitors of aminopeptidase activity are associated with macrophage activation and differentiation, Bestatin has shown significant therapeutic effects in several clinical trials.91 In a multi-institutional study,92 patients with acute non-lymphocytic leukemia (ANLL) were randomized to receive either Bestatin or placebo orally after completion of induction and consolidation therapy, and concomitant with maintenance chemotherapy. Remission duration was prolonged in the Bestatin group, although this difference did... 

Inhibitors of Enzymes Involved in GIn-tRNA and Asn-tRNA Biosynthesis as Tools for... 

Robert Chenevert is Professor of Organic Chemistry at Universite Laval, Quebec, Canada. He studied chemistry (B.Sc. and M.Sc.) at the Universite de Montreal. After receiving his Ph.D. in organic chemistry in 1975 at the Universite de Sherbrooke under the supervision of Professor Pierre Deslongchamps, he spent a postdoctoral year at Harvard (R. B. Woodward s group). His main research interest is the application of biocatalysts in asymmetric synthesis. He is also interested in the design of inhibitors of enzymes involved in the aminoacylation of tRNA (aminoacyl-tRNA synthetases and aminoacyl-tRNA amidotransferases). 

A related case is when products B and A are considered to be inhibitors of enzymes Ei and E2, respectively. When B and A compete with A and B, respectively, the following equations hold for ri and V2 [146] ... 

Of particular note is the combination of amoxicillin and clavulanic acid. The latter is a potent inhibitor of enzymes that degrade amoxicillin and many other p-lactam antibiotics. This combination, marketed as Augmentin, increases the efficacy of amoxicillin against organisms that would be otherwise resistant to it. It is among the most widely used antibiotics in the United States. 

Moderate inhibitor of enzyme. ++ Strong inhibitor of enzyme. 

There are a number of metals that are irreversible inhibitors of enzymes. Those that are found in increasing quantities in the environment and hence are causing concern include lead, mercury, cadmium and copper. Enzymes that possess the amino acid cysteine in their active site are most vulnerable, since the sulphydryl group (-SH) in this site readily reacts with the metal ions (Appendix 3.7). 

Although most of the enzyme-based drugs are inhibitors of enzymes, a number of enzyme preparations have also been developed as drugs for the treatment of a number of diseases. The development of enzymes as therapeutics has been made easier due to the advances in biotechnology. Most successful example of enzyme therapy includes various preparations of plasminogen activators (thrombolytic or fibrinolytic agents) such as a bacterial protein streptokinase and two plasminogen activators... 

Hydroxycyclopropanecarboxylic acid phosphate HCP 34 is an analogue of phosphoenolpyruvate (PEP) 35 which is metabolized by various enzymes. HCP 34 is a potent competitive inhibitor of enzymes utilizing PEP 35, such as PEP carboxylase, enolase, pyruvate kinase, and probably other enzymes. It is a substantially better inhibitor than phospholactate 36 or phosphoglycolate 37, presumably because of the similarity of its geometric and electronic structures with phosphoenol pyruvate,Eq. 12 [28]. 

Exchange-inert complexes of Cr(III) with nucleotide ligands are very stable toward hydrolysis. Such complexes have proven to be extremely useful as chirality probes in that different coordination isomers can be prepared and separated These nucleotide complexes have also proved useful as dead-end inhibitors of enzyme-catalyzed reactions. Because Cr(lII) is paramagnetic, distances can be measured by measuring the effects of Cr(lll) on the NMR signals of nearby atoms when the Cr(lll)-nucleotide complex binds to the surface of a mac-romolecule. See Exchange-Inert Complexes... 

A graphical protocol for the analysis of tight-binding inhibitors of enzyme-catalyzed reactions (see figure) . ... 

An alkylating agent (ICH2COO ) that acts as a potent irreversible inhibitor of enzymes containing reactive thiol, e-amino, and/or imidazole side-chain groups within their active sites. The carboxymethylation reaction with enzymes is typically a bimolecular process that takes place without rate-saturation behavior ... 

A molecule designed to mimic the properties, structure, and/or geometries of the transition state of a particular reaction. Such compounds are often potent inhibitors of enzymes. See Molecular Similarity... 

Among bicyclic compounds mercapto amide 394b is one of the most potent substances (96JME494,97JME1570). Amidolactam 362, on the other hand, is an excellent selective, reversible inhibitor of enzymes caspase-1 and caspase-3 (98BML2757). 

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