Actions of inhibitors

In another study, cyanide inhibited the oxidation of D- and L-lactate and NADH oxidase activity in membrane particles of P. shermanii (Pritchard and Asmundson, 1980). The oxygen uptake insensitive to the inhibition by 100 iiM KCN amoimted to 30, 15, 80 and 10% of the total oxygen uptake with L-lactate, D-lactate, succinate and NADH as substrates, respectively. Cyanide-resistant respiration is widespread among living organisms. It is attributed to flavoprotein respiration with participation of oxidases resistant to KCN (Beevers, 1961) it is also explained by die presence of a 6-shimt, i.e., a by-pass to oxygen from cytochrome b (see below). 

Organism Oxygen uptake, nmol 02/mg dry weight per min Inhibition, %  

Since only 30-50% of the CN-resistant respiration results in H2O2 formation, the existence of an alternative system of CN-resistant oxidases and peroxidases was suggested. Peroxidase activity is found in propioni-bacteria (Vorobjeva et al., 1986). Since CN-resistant oxidases have a low 

Other oxidase inhibitors, such as CO and NaNs, only slightly affected the respiratory activity of the cultures (Bonarceva et al., 1973a, b). The data mentioned above show that propionic acid bacteria do not have a typical cytochrome oxidase sensitive to CO and KCN. The peculiarity of the propionibacterial respiration is also expressed (Chaix and Fromageot, 1939) in that it is stimulated by H2S, similar to chloreUa, but unlike the respiration of other microorganisms. 

4-Dinitrophenol and gramicidin, uncouplers of the oxidative phospho-r lation in mitochondria, also suppressed the respiration in propionibacteria. Especially sensitive to the action of imcouplers were cells of P. petersonii, in which the respiration was completely blocked by gramicidin at 10 p g/ml, while in P. shermanii it was inhibited by 93% at 100 iig/ml gramicidin. Dinitrophenol at a concentration of MO M decreased the rate of respiration by 40% in P. shermanii, but blocked it completely in P. petersonii. 

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Composition of the liquid environment The ionic composition, arising from dissolved salts and gases, has a considerable influence on the performance of inhibitors. In near-neutral aqueous systems the presence of certain ions tends to oppose the action of inhibitors. Chlorides and sulphates are the most common examples of these aggressive ions, but other ions, e.g. halides, sulphides, nitrates, etc. exert similar effects. The concentration of inhibitor required for protection will depend on the concentrations of these aggressive ions. Laboratory tests " have given some quantitative relationships... 

Although halide ions are aggressive in near-neutral solutions they can be used to improve the action of inhibitors in acid corrosion (see Practice Acid Solutions). Variations exist among the halides, e.g. chloride ions favour the stress-corrosion cracking of Ti in methanol whereas iodide ions have an inhibitive action ... 

The four mechanisms discussed above, of the action of inhibitors remain essentially unchanged. Further work on acetylenic alcohols has indicated that barrier films can form owing to crosslinking by hydrogen bonding and synergistic interactions . Theoretical treatments of the electrochemical... 

The mechanisms of action of inhibitors which form salt films on metals have been reviewed. ... 

A second principle used widely for glucose analysis, is that of the oxidation of glucose enzymatically, mediated by the action of glucose oxidase with the formation of gluconic acid and hydrogen peroxide (22). In this procedure it is the hydrogen peroxide which is usually assayed for determination of glucose. This method suffers from the action of inhibitors which occur, particularly with patients in a diabetic coma and these need to be removed. 

Fig. 3 AchE-biotests after normal colour reaction and after action of inhibitors...

In some cases, as in case of diphenyl picryl hydrazide (DPPH), the action of inhibitor may be due to the fact that it can exist in the form of stable free radicals which stops the chain growth by direct coupling. 

Partial reactions. Through the use of various electron donors and acceptors, it is possible to bracket specific sites on the electron-transport pathway associated with the action of inhibitors (23-25). Attempts to identify the slte(s) of interaction of the allelochemlcals on the electron-transport pathway were generally... 

Thus, the effects of glycosylation inhibitors on intact cells may also be studied best with virus-infected cells. Before release of virus, the glycoproteins are detected in the water-insoluble, membranous fraction. Furthermore, the lipid-linked oligosaccharides may be rather specifically extracted from whole cells, and monosaccharide-lipids may also be determined.3-116 It is thus seen that the various tools of virology and of lipid and carbohydrate biochemistry have proved productive in establishing the mode of action of inhibitors of lipid-depen-dent glycosylation of proteins. 

The most direct evidence that negative catalysis sometimes works in this way in ordinary thermal reactions, and, therefore, incidentally that the chain mechanism can operate in such reactions, has been found by Backstrom. In the photochemical oxidation of benzaldehyde, heptalde-hyde, and of solutions of sodium sulphite, there are very large numbers of molecules transformed for each quantum of light absorbed, amounting respectively to 10,000,15,000, and 50,000 for the three reactions. Such deviations from Einstein s law show that the light probably sets up chain reactions. These photochemical changes are markedly subject to the action of inhibitors, which presumably cut short the chains. Backstrom establishes the important... 

For II, the induction period action of inhibitors and kinetic complexity all point to a free radical oxidation. This is not to say that the addition-elimination mechanism does not occur, but it must be slow and even in the absence of 02 is blocked by the formation of stable allylic complexes. Since cyclohexene is also an internal olefin, one might expect similar reactivity to II. This is not the case in chloride-free media since cyclohexenylpalladium acetate complexes are unstable and decompose to 2-cyclohexen-l-yl acetate (14, 15). 

The Enzyme Commission catalog (EC 3.5.1.5) lists the urease reaction as urea + 2 H20 = C02 + 2 NH3. Since two C-N bonds are broken it is evident that the stoichiometric relation above is the result of two component reactions. Any conjecture concerning the mechanisms of these reactions and the nature of the intermediates must encompass the action of inhibitors and the spectrum of substrates. Some of the organic inhibitors that have been reported are shown in Table I. The substrates that have been shown to be hydrolyzed are listed in Table II. 

Modifying Effects of Detergents on the Action of Inhibitors, in Vitro... 

Where rather detailed studies have been made, it has been found that the actions of inhibitors on enzymic activities often are quite significantly affected by such factors as reaction pH and the presence of... 

The action of inhibitors is intermediate between very strong irreversible poisoning and the normal competition between molecules for a given active site. The sensitivity to inhibitors can thus be expressed either as in the case of poisons (and then a/cp can be used), or as in the case of competition (e.g., by a classical Lang-muir-Hinshelwood formulation). In the latter case, for example, the value, or relative value, of the adsorption coefficient could characterize the inhibitor. 

Thcnoyltrifluoroacetone Fig. 14-3 Sites of action of inhibitors of the electron-transport chain. 

Cm, ca - numbers of growing, kariokynetic and atypical cells ai, a2 - coefficients of auto-inihibition at the expense of competition for general resource between growing, kariokynetic and atypical cells pn, pa - coefficients of growth of normal and atypical cells b - coefficient of population chain branching d - rate of atypical cells extinction f, f2 - coefficient of kariokynetic and atypical cells reproduction x - inhibitor concentration i, 2, 53, S4 -coefficient of toxic action of inhibitor on corresponding process. 

Even for antimicrobial drugs wich have the same mode of action, the mechanisms of actions in molecular terms can be quite different. An instructive example of this is the body of knowledge on actions of inhibitors of protein synthesis at the ribosomal level66). Since the mechanistic details of protein biosynthesis as well as of DNA replication are still incompletely resolved, studies on mechanisms of action of inhibitors of these biosynthetic processes frequently remain inconclusive when the target reaction is not known. Each problem of the mechanism of action of a chemotherapeutic drug becomes an individual research problem in its own right, after the mode of action has been elucidated in the manner described in this article. 

The elucidation of the primary site and biochemical mode of action of inhibitors is often difficult and not necessarily associated with the mechanism of resistance in field isolates. Nevertheless, information on the mechanism of resistance can provide evidence to determine the site of action. Therefore, the classification of fungicides is based on crossresistance reactions rather than chemical similarities of structures or proposed modes of action (Table 1). Based on available information in the literature, three categories of inhibitor classes can be made Classes with known mode of action and known mechanism of resistance, classes with proposed mode of action and unknown mode of resistance but wide-spread field resistance, and classes in which resistance is claimed to occur in the field but both mode of action and resistance are not known. 

Hugues, J., Mode of Action of Inhibitors of Platelet Adhesion to Col-... 

Using the technique of differential calorimetry, Kapralova has found evidence that, the initiation and termination of chains in 1,2-dichloroethane pyrolysis occurs on the reaction vessel walls instead of in the homogeneous gas phase. It has also beenproposed - that the inhibitory effect of propene may be associated with its absorption on the vessel walls causing a reduction in the rate of the initiation of chains on the surface. The mechanism of chain initiation and the action of inhibitors and sensitisers in 1,2-dichloroethane pyrolysis have been further discussed in papers by Kapralova and Semenov > Kitabatake and Onouchi and Smolyan . 

The mode of action of inhibitors can be divided into two groups reversible or irreversible. A detailed explanation can be found in textbooks of enzyme kinetics and assays [345]. The critical aspects and kinetics of both mechanisms are summarized in Table 10.8. In brief, in all cases the presence of a substrate is a prerequisite and it has to be added at a concentration that does not hmit the reaction rate of the non-inhibited... 

The aim of this review is to outline the drugs that are currently available and the medicinal chemistry that led to their discovery. The physiological processes associated with acid secretion and the mechanism of action of inhibitors of this process are described. Current research into inhibitors of gastric acid secretion is aimed at producing a reversible PPI or antagonist of receptor-mediated acid secretion. The medicinal chemistry and pharmacology of such approaches are considered. 

Other theories that have been evolved also consider the action of inhibitors to be through the destruction of active intermediate oxidation products, such as peroxides, and the resultant interruption of a chain of reactions which normally would have involved many molecules of the oxidizable substance. Such theories differ principally in the mechanism through which peroxide destruction and chain interruption are brought about without the total concomitant destruction of the inhibitor.54... 

It may be noted that other steps in the metabolic sequence are subject to the action of inhibitors, some of which appear in medical folklore as anticancer agents. 

Although direct observation of the microcirculation is not possible in the standard IPRK model, the use of hyperoncotic solutions to create a non-filtering kidney [169] allows a relatively clean interruption of tubuloglomerular feedback (by impairing distal tubular NaCl delivery) analogous to papillectomy in the perfused juxtameduUary nephron technique [101]. Frusemide can also be used to inhibit tubuloglomerular feedback in either preparation and in vivo [170]. However, the overlap with other actions of inhibitors (such as diure-... 

Figure 1 Illustration of potential sites of action of inhibitors of chemical...

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