Mixed-type inhibitors

The PL-catechin conjugate showed greatly amplified concentration-dependent inhibition activity against bacterial collagenase (ChC) on the basis of the catechin unit, which is considered to be due to effective multivalent interaction between ChC and the catechin unit in the conjugate. The kinetic study suggests that this conjugate is a mixed-type inhibitor for ChC. Hyaluronidase is an enzyme which catalyzes hydrolysis of hyaluronic acid and is often involved in a number... 

The mixed-type inhibitors combine the effects of the competitive and noncompetitive inhibitors binding at the active center decreases the affinity of the enzyme towards the substrate molecule and also decreases the rate of transformation of the bound substrate. In their presence, the straight line plots intersect in the fourth quarter of the Lineweaver-Burk plot, according to equation ... 

Cathodic inhibitors Anodic inhibitors Mixed type inhibitors... 

Icmt catalyzes the methyl esterification of the prenylated cysteine residue after Reel has proteolyzed the -CaaX-containing proteins. The first step in identification of the minimal substrate for Icmt was through identification of AFC (Figure 9.2) as described above. Interestingly, farnesylcys-teine (FC), which is devoid of the acetyl substitution, was not a substrate but did possess some activity as an inhibitor [51], suggesting that the free amine of FC requires modification for catalytic turnover. Alterations in the stereochemistry about the FC backbone also appeared to be detrimental to substrate activity. The stereoisomer, d-AFC, was not a substrate for Icmt but was a modest mixed-type inhibitor of the enzyme. AFC-methyl ester (AFC-Me) was also reported to be a mixed-type inhibitor with respect to both l-AFC and -adenosylmethionine (SAM), the methyl donor, with Ki values of 41 and 73 pM, respectively [52,53] The farnesyl homocysteine homolog of AFC is not a substrate for the enzyme however, the racemic DL-homocysteine farnesyl derivative is in fact a weak inhibitor [40]. Similar to the results with racemic prenylcysteine, these data demonstrate that the linker between the carboxylate and thioether moieties is critical for substrate activity. 

Again, this type of inhibition is rarely seen in single-substrate reactions. It should also be noted that, frequently, the affinity of the noncompetitive inhibitor for the free enzyme, and the enzyme-substrate complex, are different. These nonideally behaving noncompetitive inhibitors are called mixed-type inhibitors, and they alter not only V ax but also Km for the substrate. Further discussion of inhibitors cf this type may be found in Segel (38). 

Figure 4-32 l/v versus 1/[S] plot in the presence of different fixed concentrations of a mixed-type inhibitor (1 < a < ), ESI is catalytically inactive. K, = Ke, for rapid equilibrium conditions. 

If I and S are not mutually exclusive and both ligands bind independently of each other, I will be a noncompetitive inhibitor. If I affects the affinity of E for S, 1 will be a mixed-type inhibitor with linear slope and intercept replots. 

Equations 43, 44, and 45 tell us that at a fixed inhibitor concentration, increasing the substrate concentration (a) decreases the degree of competitive inhibition, (b) has no effect on the degree of noncompetitive inhibition, and (c) increases the degree of uncompetitive inhibition. The effect of increasing [S] on the degree of inhibition caused by a mixed-type inhibitor depends on the interaction factor, a. In the usual case of ct > 1, the degree of inhibition decreases as [S] increases at a fixed [I]. 

The sensitivity of rate coefficients to structural changes in substrate or inhibitor, to covalent modifications of the enzyme either at sites proximate to, or distal to, the active site, to pH changes etc. does provide a powerful probe. The pH dependence of individual steps in a mechanism for an enzyme can sometimes now be isolated, the sites of action in a reaction pathway of complex (e.g. mixed type) inhibitors can... 

Although enzyme reactions are highly specific, inhibition of the enzymes do occur. Inhibitors, substances that decrease the rate of an enzyme-catalyzed reaction, are classified as competitive, noncompetitive, uncompetitive, or mixed [4]. Each type can be characterized by deviation from the Lineweaver-Burk plot of the corresponding uninhibited reaction. Competitive inhibitors compete for the active sites with the substrate and slow down the enzyme reaction they increase Km but have no affect on Vmax- Noncompetitive inhibitors bind reversibly to the enzyme at a site different from the active site, but one that is necessary for the enzyme action. These inhibitors decrease Emax, but Km is unaffected. Uncompetitive inhibitors are known to bind reversibly to the enzyme-substrate complex to form an inactive enzyme-substrate-inhibitor complex. A decrease in Km and max by the same factor is observed (i.e., the Lineweaver-Burk plot is parallel to the plot of the uninhibited reaction). In mixed-type inhibitors, more than one of the foregoing mechanisms operate, and Km and Lmax values are both altered. 

Inhoff Oliver, R. J. M. Briet, I.W. Lowe, G. Krauth-Siegel, R. L. Coupling of a competitive and an irreversible ligand generates mixed type inhibitors of Trypanosoma cruzi trypanothione reductase. J. Med. Chem. 2002, 45, 4524-4530. 

In the case of HCl media, all ILs studied, mainly [C4mim] and other imidazole or pyridinium derivatives, regardless of the type of anion, showed the same behaviour, acting as mixed-type inhibitors. EIS data showed that inhibition takes place by strong adsorption obeying Langmuir adsorption isotherm. This adsorption has a more physical than chemical character and, based on the AG and AH values, the adsorption process is spontaneous and exothermic. 

In sulphuric media, all the imidazolium and pyridinium derivatives smdied showed similar behaviour to that observed in HCl, as mixed-type inhibitors forming a monolayer on the surface through Langmuir isotherm, but in this case AG values are around —40 kJ moP, indicating a higher chemical adsorption character corresponding to sharing of transfer of electrons from the inhibitor molecules to the metal surface to form a coordinated type of bond. Scheme 19.1 represents the inhibition mechanism proposed by Likhanova et al. [32]. 

Five withanolides isolated from Withania somnifera [mdAjuga bracteosa Benth. (Lamiaceae)] were shown to be novel natural cholinesterase (AChE) inhibitors with spasmolytic and calcium antagonistic properties. Thus, they represent leads or even possible drug candidates for treatment of Alzheimer s disease or related dementia (Choudhary et al. 2004, 2005). Three withanolides were found to be linear mixed-type inhibitors of AChE, the remaining two were non-competitive inhibitors, whereas all... 

The electrochemical studies of the corrosion inhibition process of Al-Mg-Si alloy in seawater using three selected natural products as corrosion inhibitors show that the corrosion rate of the alloy significantly reduced upon the addition of studied inhibitors. PP measurement reveals that the studied inhibitors can be classified as mixed-type inhibitors without changing the anodic and cathodic reaction mechanisms. The inhibitors inhibit both anodic metal dissolution and also cathodic hydrogen evolution reactions. 

Normalization of the rate equation by total enzyme concentration (v/[Er]) and rearrangement results in the following expression for the velocity of an enzymatic reaction in the presence of a linear mixed type inhibitor ... 

Some mixed-type inhibitors (like many organic compounds) provide protection by... 

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