Enzyme-inhibitor association

For a soluble enzyme that is not part of a multi-enzyme complex, the fastest rate of enzyme-inhibitor association is determined by the rate of molecular collisions between the two binding partners (i.e., the enzyme and the inhibitor) in solution. The rate of molecular collisions is in turn controlled by the rate of diffusion. The diffusion-limited rate of molecular collisions is dependent on the radii of the two binding molecules and the solution temperature and viscosity (Fersht, 1999) ... 

H. Resat, T. J. Marrone, and J. A. McCammon, Enzyme-inhibitor association... 

Brown NJ, Ray WA, Snowden M, Griffin MR. Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Chn Pharmacol Ther 1996 60(1) 8-13. 

Burkhart DG, Brown NJ, Griffin MR, Ray WA, Hammerstrom T, Weiss S. Angiotensin converting enzyme inhibitor-associated angioedema higher risk in blacks than whites. Pharmacoepidemiol Drug Sat 1996 5(3) 149-54. 

Bakris GL and Weir MR. Angotensin-converting enzyme inhibitor-associated elevations in serum creatinine. Arch Intern Med... 

Bangalore S, Kumar S, Messerlu FH. Angiotensin-converting enzyme inhibitor associated cough deceptive information from the Physicians Desk Reference. Am J Med 2011 123 1016-30. 

Piezoelectric measurements use the appearance of an electrical polarization, or a variation in an existing polarization, in certain anisotropic dielectric materials, for example, quartz. This polarization appears when a force is applied in the appropriate direction. The piezoelectric effect is reversible because the material can deform or vibrate when an electric field is applied in the appropriate direction. Piezoelectric devices are used at their resonance frequencies for the determination of small variations in mass. These variations may result firom biological reactions that involve association or coupling, for example, enzyme-inhibitor associations or antigen-antibody coupling. 

Enzyme inhibitors are classified in several ways. The inhibitor may interact either reversibly or irreversibly with the enzyme. Reversible inhibitors interact with the enzyme through noncovalent association/dissociation reactions. In contrast, irreversible inhibitors usually cause stable, covalent alterations in the enzyme. That is, the consequence of irreversible inhibition is a decrease in the concentration of active enzyme. The kinetics observed are consistent with this interpretation, as we shall see later. 

A case similar to the slow, practically irreversible inhibition of jack bean a-D-mannosidase by swainsonine is represented by the interaction of castanospermine with isomaltase and rat-intestinal sucrase. Whereas the association constants for the formation of the enzyme-inhibitor complex were similar to those of other slow-binding glycosidase inhibitors (6.5 10 and 0.3 10 M s for sucrase and isomaltase, respectively), the dissociation constant of the enzyme-inhibitor complex was extremely low (3.6 10 s for sucrase) or could not be measured at all (isomaltase), resulting in a virtually irreversible inhibition. Danzin and Ehrhard discussed the strong binding of castanospermine in terms of the similarity of the protonated inhibitor to a D-glucosyl oxocarbenium ion transition-state, but were unable to give an explanation for the extremely slow dissociation of the enzyme-inhibitor complex. 

Gelman BB, Wolf DA, Rodriguez-Wolf M et al (1997) Mononuclear phagocyte hydrolytic enzyme activity associated with cerebral HIV-1 infection. Am J Pathol 151 1437-1446 Giraudon P, Buart S, Bernard A et al (1997) Cytokines secreted by gUal cells infected with HTLV-I modulate the expression of matrix metalloproteinases (MMPs) and their natural inhibitor (TIMPs) possible involvement in neurodegenerative processes. Mol Psychiatry 2(107-10) 84... 

Let us assume that for a particular enzyme-inhibitor pair, association is diffusion limited so that k, is I O9 M s1. Fixing k n at this value, and using Equation (7.26), we can determine the value of koB for different values of Kn as summarized in Table 7.3 (this is taken from the more comprehensive table presented in Chapter 2). We have already seen examples in Chapter 6 of compounds with A) values (or Kf values) in the lOnM to lOpM range for which the half-life for binary complex dissociation is far longer than 2 hours. For example, we saw that inhibition of COX2 by DuP697 resulted in a final E I complex with Kf = 5 nM and the lm for complex... 

Table 7.3 Values of k for different values for enzyme-inhibitor binary complexes when the rate of complex association is diffusion-limited (k = I09M W)...

Elevated blood pressure is common after ischemic stroke, and its treatment is associated with a decreased risk of stroke recurrence. The Joint National Committee and AHA/ASA guidelines recommend an angiotensin-converting enzyme inhibitor and a diuretic for reduction of blood pressure in patients with stroke or TIA after the acute period (first 7 days). Angiotensin II receptor blockers have also been shown to reduce the risk of stroke and should be considered in patients unable to tolerate angiotensinconverting enzyme inhibitors after acute ischemic stroke. 

In enzyme catalyzed reactions the inhibitor may interact in various ways either reversibly or irreversibly. In irreversible inhibition, the inhibitor associates with enzyme and block the active site of the enzyme or form a unstable complex with enzyme and thus retards the rate of reaction. 

K10. Keilani, T., Schlueter, A., Levin, M. L., and Battle, D. C., Improvement of lipid abnormalities associated with proteinuria using fosinopril, an angiotensin-converting enzyme inhibitor. Ann. Intern. Med. 118, 246-254 (1994). 

EC 3.1.6.1) is a lysosomal enzyme that hydrolyzes sulfuric acid ester bonds. The enzyme exists in two forms, arylsulfatases A and B, that differ in substrate specificity and in sensitivity toward inhibitors [142][143]. Human tissues contain more arylsulfatase A than arylsulfatase B. The natural substrates of these enzymes are complex lipids such as cerebroside 3-sulfate, and gly-cosaminoglycans such as chondroitin 4-sulfate and derman sulfate [144], Deficiencies of these enzymes are associated with a number of lysosomal disorders. 

There is an increased risk of hyperkalaemia when ciclosporin is given with Coversyl, which contains perindopril, an angiotensin-converting enzyme inhibitor. Risk of nephrotoxicity associated with ciclosporin is increased with concomitant use with quinolones. Ciproxin contains ciprofloxacin, which is a quinolone. Tenormin contains atenolol, which is a beta-adrenoceptor blocker and there are no interactions between these agents and ciclosporin. 

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