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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
In uncompetitive inhibition, the second type of allosteric binding mechanism (see above) and formally the counterpart of competitive inhibition, the inhibitor exclusively binds to the ES-complex, which means that substrate binding is required for the formation of an inhibitor binding site. The initial reaction rate is given by
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Published in Calver Pang, Ibraz Hussain, John Mayberry, Pre-Clinical Medicine, 2017
Calver Pang, Ibraz Hussain, John Mayberry
This question focuses on diabetes. Blood sugar levels in diagnosing diabetes are different dependent on the plasma glucose test. In a random glucose test or a 2-hour postprandial test, a level of 11.1 mmol/L is diagnostic whereas a fasting glucose test level of 7.0 mmol/L or more is diagnostic. Insulin is a hormone that has many physiological effects not only on carbohydrate metabolism but also lipid (increases lipogenesis and decreases lipolysis) and protein (increases protein synthesis and decreases protein degradation) metabolism. Enzyme kinetics is a common exam topic and it is important to appreciate that a competitive inhibitor increases Km but has no effect on Vmax; an uncompetitive inhibitor decreases both Km and Vmax; a non-competitive inhibitor has no effect on Km but decreases Vmax.
In Vitro to In Vivo Extrapolation of Metabolic Rate Constants for Physiologically Based Pharmacokinetic Models
Published in John C. Lipscomb, Edward V. Ohanian, Toxicokinetics and Risk Assessment, 2016
The inhibition term in Eq. (20) modifies [S]. Division of both denominators of Eq. (20) by (1 + [I]/KI) results in the inhibition term dividing both Vmax and KM. Unlike competitive inhibitors, the extent of inhibition by an uncompetitive inhibitor increases with increasing substrate concentration. This is because there is a greater concentration of the ES complex at higher substrate concentrations (6). Double reciprocal plots of initial rate data obtained in the presence of different concentrations of an uncompetitive inhibitor are a series of parallel lines (Fig. 2). At high enough concentrations, uncompetitive inhibitors can drive the reaction velocity to zero (6). Uncompetitive inhibitors are rare in nature. Considering the devastating effects an uncompetitive inhibitor could have on cellular function, it has been suggested that evolution has selected against enzymes that are prone to uncompetitive inhibition (10).
Mixed and non-competitive enzyme inhibition: underlying mechanisms and mechanistic irrelevance of the formal two-site model
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
The Michaelis–Menten model was derived for single substrate reactions, although these are quite rare in biochemistry and are confined to a few isomerizations. It has been evaluated that some 60% of all the known enzyme-catalyzed reactions involve the conversion of two substrates into two products according to the equation A + B = P + Q6. For such reactions, referred to as Bi-Bi reactions, there are three common mechanisms: the substituted-enzyme (or ping-pong) mechanism and the ternary-complex mechanism, either with compulsory or random order of substrate binding. Depending on the actual mechanism, the steady-state analysis of a dead-end inhibitor directed against the binding site of substrate A and assayed against substrate B (i.e. at varying B concentrations and at fixed A) can give mixed-type, pure non-competitive or uncompetitive inhibition. This is a very well-established fact47–49 that likely constitutes the most common source of non competitive inhibition. Here, we sought to demonstrate whether in this mixed inhibition case too, the uncompetitive inhibition constant,
Investigation of the enantioselectivity of acetylcholinesterase and butyrylcholinesterase upon inhibition by tacrine-iminosugar heterodimers
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
I. Caroline Vaaland, Óscar López, Adrián Puerta, Miguel X. Fernandes, José M. Padrón, José G. Fernández-Bolaños, Magne O. Sydnes, Emil Lindbäck
The inhibition modes of eeAChE and eqBuChE by heterodimer 11b were investigated by using the Cornish-Bowden method, that is, by creating two plots (1/V vs. [I] and [S]/V vs. [I]) for the inhibition of both enzymes (Figure 3). The two plots for the inhibition of each enzyme included a point of intersection at different [I]-coordinates, which implies that 11b is a mixed inhibitor of both enzymes47. The competitive inhibition constant, Ki, and uncompetitive inhibition constant, αKi, for eeAChE by 11b is 19.0 ± 1.8 nM and 21.9 ± 7.2 nM, respectively. The inhibition constants of eqBuChE are Ki =10.0 ± 2.7 nM and αKi = 14.3 ± 3.3 nM. The mixed inhibition modes of eeAChE and eqBuChE by 11b were interpreted to indicate that 11b behaves as a dual binding site inhibitor of both enzymes; it is tempting to think that 11b binds simultaneously to the active site and PAS of both eeAChE and eqBuChE. However, in this context it is worth mentioning that the architecture of PAS in the two enzymes is different as it is richer on aromatic amino acid residues in eeAChE48,49, which allow formation of π–π interactions and cation–π interactions with ligands50.
Tissue and interspecies comparison of catechol-O-methyltransferase mediated catalysis of 6-O-methylation of esculetin to scopoletin and its inhibition by entacapone and tolcapone
Published in Xenobiotica, 2021
Aaro Jalkanen, Veera Lassheikki, Tommi Torsti, Elham Gharib, Marko Lehtonen, Risto O. Juvonen
The esculetin 6-O-methylation rate (v) was calculated using the equation v = p/(time × protein), where p is the amount of product, time is the time for product formation, and protein is the mass of protein in the sample. The IC50 value (inhibitor concentration decreasing 50% of the activity) was calculated using the equation vi/v0 = 1/(1 + IC50/I), where vi is the rate in the presence of an inhibitor, v0 the rate without an inhibitor, and I is the inhibitor concentration. The competitive inhibitor constant Kic and uncompetitive inhibitor Kiu constants were calculated using the equation IC50 = (S + Km)/(Km/Kic + S/Kiu) + E/2, where S is the substrate concentration, Km is the Michaelis constant being 0.36 µM for esculetin, and enzyme concentration E varied as indicated in the simulation (Table 4).