Inhibition by metal complexes

In zinc metalloenzymes. zinc is a selective stoichiometric constituent and is essential for catalytic activity. It is frequently present in numerical correspondence with the number of active enzymatic sites, coenzyme binding sites, or enzyme subunits Removal of zinc results in loss of activity. Inhibition by metal complexing agents is a characteristic feature of zinc metalloenzymes. However, no direct relationship holds between the inhibitory effectiveness of these agents and their affinity for ionic zinc. Although zinc is the only constituent of zinc metalloenzymes in vivo, it can be replaced by other metals m vitro, such as cobalt, nickel, iron, manganese, cadmium, mercury, and lead, as m the case of carboxy-peprida.ses. 

An interesting variation where the photo-BC is inhibited by metal complexation is described by O Connor et al. [30] (Scheme 30.17). In contrast to the parent benzannelated cyclic enediyne, its ruthenium complex did not produce any cyclized product upon photoactivation. The reluctance of this compound to be involved in photochemical cycloaromatization is tentatively attributed to decreased aromaticity in the incipient 1,4-diradical, potentially providing an interesting corollary to the results summarized in Scheme 30.7. 

Metal Deactivators. The abiUty of metal ions to catalyse oxidation can be inhibited by metal deactivators (19). These additives chelate metal ions and increase the potential difference between the oxidised and reduced states of the metal ions. This decreases the abiUty of the metal to produce radicals from hydroperoxides by oxidation and reduction (eqs. 15 and 16). Complexation of the metal by the metal deactivator also blocks its abiUty to associate with a hydroperoxide, a requirement for catalysis (20). 

Divalent metal ions inhibit the hydrolysis of N-(2-pyridyl)phthalamic acid (60) and N-(2-phenanthrolyl)phthalaxnic acid (61). In the case of (61) the substrate hydrolyzes by a pathway involving intramolecular general acid catalysis, and this pathway is inhibited by metal ions. Deprotonated amide complexes may also be involved leading to catalytically inactive complexes. 

The phenomenon of catalyst-inhibitor conversion1 2,143,356 may be understood and critical concentration of metal can be deduced by reference to Eq. (280). If decomposition of the hydroperoxide is the source of initiation, it must be formed as rapidly as it is consumed to maintain a steady rate. If termination by metal complex predominates, a steady state occurs when the right-hand side of Eq. (280) equals unity. No oxidation will occur when this quantity is less than unity. Hence, catalyst-inhibitor conversion is observed as the metal concentration is increased to the point that the chain length becomes less than unity. If termination occurs by the bimolecular reaction of peroxy radicals, a chain length of less than unity will result in the depletion of the hydroperoxide until the rate of initiation has decreased to the point where the chain length is unity again. No inhibition is expected or observed. 

D-Lactate cytochrome c reductase is inhibited by p-mercuriphenyl sulfonate salts, metal chelators, and dicarboxylic acids such as oxalate and oxaloacetate (Table XVI) (312, 314, 315). According to Nygaard (314), salts (cations) inhibit at the acceptor site, and dicarboxylic acids at the substrate site. Cremona and Singer (315) have studied the inhibitions by metal chelators and by oxalate. They recognized two types of inhibition. One type of inhibition is that which is caused by EDTA or oxalate. This kind of inhibition is reversed immediately upon dilution of the enzyme-inhibitor mixture. The second is that which results from addition of o-phenanthroline. Enzyme preparations treated with o-phenanthroline bind 2 moles of the chelator per mole of Zn . This complex is stable and inactive, and does not result in the release of Zri . The inactive... 

It could be shown, moreover, (Vallee and Neurath, 1955) that five times recrystallized carboxypeptidase was completely inhibited by metal chelating agents, such as 8-OHQ-5SA and 1-10 phenthroline at concentrations of 10 W,Q ,Q Dat concentrations of 10" Af, and some 30% byEDTA at 10 M. These are all known to form complexes with zinc in simple systems. In these experiments, the buffered enzyme solutions were incubated with the chelating agent at pH 7.5, 4°C., for 1 hour prior to the addition of the substrate. Inhibition did not occur when these chelating agents were first incubated with an equimolar amount of zinc, cupric, or ferrous ions. Sodium diethyldithiocarbamate, zincon, sulfanilamide, and diamox, the latter two employed because of their effect on carbonic anhydrase, had little, if any, effect on carboxypeptidase activity. DPN, nicotinamide, and A-methylnicotinamide, examined because of their effect on the ADH sys-... 

Since the effects of heavy metals increase the amount of free radicals in the lipid phase, not only do the rates of initiation and propagation reactions increase, but also the rate of termination reaction increases. Heavy metals therefore also change the composition of the reaction products. At high concentrations of free radicals, the termination reaction may dominate and metals then act as the inhibitors of autoxidation. Autoxidation reaction can also be inhibited by metals when they are present at higher concentrations. It is assumed that the reason is the oxidation and reduction of free hydrocarbon radicals to anions and cations by ions of Fe and Cu and the formation of complexes of free radicals. Other complexes are also formed with Co. All these reactions interrupt the radical chain autoxidation reaction. Reactions with Fe ions are given as examples. 

Hydrogenation using the rhodium complex may involve the formation of colloid particles, as it was shown that the reaction is inhibited by metallic mercury [167]. Selective hydrogenation of the carbonyl group in a,P-unsatu-rated carbonyl compounds can be done with immobilized ruthenium or iridium complexes by using either the supported aqueous phase technique... 

Silicates. For many years, siUcates have been used to inhibit aqueous corrosion, particularly in potable water systems. Probably due to the complexity of siUcate chemistry, their mechanism of inhibition has not yet been firmly estabUshed. They are nonoxidizing and require oxygen to inhibit corrosion, so they are not passivators in the classical sense. Yet they do not form visible precipitates on the metal surface. They appear to inhibit by an adsorption mechanism. It is thought that siUca and iron corrosion products interact. However, recent work indicates that this interaction may not be necessary. SiUcates are slow-acting inhibitors in some cases, 2 or 3 weeks may be required to estabUsh protection fully. It is beheved that the polysiUcate ions or coUoidal siUca are the active species and these are formed slowly from monosilicic acid, which is the predorninant species in water at the pH levels maintained in cooling systems. 

While these calculations provide information about the ultimate equilibrium conditions, redox reactions are often slow on human time scales, and sometimes even on geological time scales. Furthermore, the reactions in natural systems are complex and may be catalyzed or inhibited by the solids or trace constituents present. There is a dearth of information on the kinetics of redox reactions in such systems, but it is clear that many chemical species commonly found in environmental samples would not be present if equilibrium were attained. Furthermore, the conditions at equilibrium depend on the concentration of other species in the system, many of which are difficult or impossible to determine analytically. Morgan and Stone (1985) reviewed the kinetics of many environmentally important reactions and pointed out that determination of whether an equilibrium model is appropriate in a given situation depends on the relative time constants of the chemical reactions of interest and the physical processes governing the movement of material through the system. This point is discussed in some detail in Section 15.3.8. In the absence of detailed information with which to evaluate these time constants, chemical analysis for metals in each of their oxidation states, rather than equilibrium calculations, must be conducted to evaluate the current state of a system and the biological or geochemical importance of the metals it contains. 

In contrast to the effects obtained with viruses mentioned earlier, rous sarcoma virus (RSV) is inactivated by direct contact with 2 [81]. Evidence for the drug action by a chelate compound was obtained by using concentrations of 3a and copper(II) sulfate, neither of which individually affected enzyme activity or transforming abilities [82]. In a later study these workers showed that several metal complexes inhibit the RNA dependent DNA polymerases and the transforming ability of RSV, the most active compound being a 1 1 copper(II)... 

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