Atypical kinetics

More recent theoretical work has raised questions about these conclusions, how-ever. Particularly extensive calculational treatment of the rearrangement of 54 to vinyl chloride by several research groups failed to duplicate the predictions of an atypical kinetic isotope effect. These later studies indicate that tunneling effects should indeed be greater for H-shift than for the heavier D rearrangement. Consequently, the k /ko ratio should actually decrease at higher temperatures. The discrepancy in predicted results was eventually traced to an error in the earlier calculations. Nevertheless, it... 

J. M. Hutzler, T. S. Tracy 2002, (Atypical kinetic profiles in drug metabolism reactions), Drug Metab. Dispos. 30(4), 355. 

An interesting aspect to CYP3A4-mediated drug oxidations is the susceptibility of the enzyme to exhibit a variety of atypical kinetic profiles including positive... 

The architecture of various CYPs may accommodate entities of different shapes [139]. Several CYPs, particularly CYP3A4 [140,141] and CYP2C9 [142], may exhibit atypical (non-Michaelis-Menten) kinetics such as heterotropic activation, homotropic activation, substrate inhibition and partial inhibition, all in a substrate-effector-dependent manner [143]. Several hypotheses have been proposed to account for the observation of atypical kinetics, including simultaneous occupancy of the CYP active site by two substrates (or one substrate and one effector simultaneously) [144] and allosteric changes in CYP architecture due to binding of an effector [145,146]. Along... 

VI. INFLUENCE OF ATYPICAL KINETICS ON INHIBITION AND DRUG INTERACTION STUDIES... 

Finally, investigators also have used the Eadie-Hofstee plot to estimate enzyme kinetic parameters (Fig. 4.4). In this last case, v is plotted along the y-axis and v/[S] along the x-axis. The slope of the best-fit line is equal to —K, the y-intercept = Umax and the x-intercept = Vmax/ m- As opposed to the double-reciprocal plot, the Eadie-Hofstee plot can make good data look worse (Dowd and Riggs, 1965). Interestingly, another use of the Eadie-Hofstee plot is to diagnose atypical kinetic profiles based on the shape of the data-fit obtained. This will be discussed in detail later in the chapter. 

Pseudocholinesterase (EC 3.1.1.8). Enzyme present in serum but shows atypical kinetics Condition first discovered with introduction of suxamethonium (suc-cinyl dicholine) as muscle relaxant in electroconvulsion therapy. This drug is normally rapidly hydrolysed by pseudocholinesterase, and its effects last only a few minutes Afiected subjects (1 in 2,000 Europeans) develop prolonged muscular paralysis and apnea (up to 2 hours) after normal drug dose. Condition screened for by measuring inhibition of serum cholinesterase by dibucaine percent inhibition is called dibucaine number (80% for normal enzyme, 20% for atypical enzyme at lO M dibucaine). Dibucaine nmnbers of about 62 % also occur in 4 % of Europeans, who possess about equal amounts of normal and atypical forms... 

Kasai N, Ikushiro S, Hirosue S, Arisawa A, Ichinose H, Uchida Y, Wariishi H, Ohta M, Sakaki T (2010) Atypical kinetics of cytochromes P450 catalysing 3 -hydroxylation of flavone from the white-rot fungus Phanerochaete ehrysosporium. J Biochem 147 117-125... 

In the course of the last 10 years, we have studied the kinetics of the HA hydrolysis catalyzed by HAase. An atypical kinetic behavior was observed whose extent varied according to the experimental conditions used. We then showed that, in fact, to properly describe the behavior of the HA/HAase system, the ability of HA to form electrostatic complexes with proteins, including HAase, should be taken into account in addition to the formation of the HA-HAase catalytic complexes. Our studies also showed that, as a consequence, the HAase activity towards HA can be strongly modulated by the formation of electrostatic complexes involving either HA or HAase or both. In addition to review these results and their main conclusions, we discuss here their relevance under both in vitro and in vivo situations. 

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