Kinetic isotope elfects

Kiefer, P. M., Hynes, J. T. (2006) Interpretation of primary kinetic isotope elfects for adiabatic and nonadiabatic proton transfer reactions in a polar environment, in Isotope Effects in Chemistry and Biology,... 

The observed proportions of do mjz 96), (mjz 97), and 2 mjz 98) ions result from a normal kinetic isotope elfect on the order of 3.5 for the Bronsted acid base reaction followed by a k jk of 2.8 for the subsequent atom abstraction. Cyclooctyl cations acquire symmetry due to the bridging hydrogen, as depicted, which accounts for the fact that both of the tetradeuterated precursors give the same product ion intensity ratios. After the Bronsted acid-base step, however, the cyclooctene-containing complexes are discrete and non-interconverting, which accounts for why the randomization model (equation 3) fails for this reaction. 

The variations of the secondary H/D kinetic isotope elfects with substituents, found by Gajewski and Conrad [11], provide indirect experimental evidence for the connection between the number and placement of radical stabilizing substituents and the TS geometry. Direct computational evidence comes from the calculated dependence of R in the Cope TS on the number and placement of cyano [27] and phenyl [28] groups. This dependence is illustrated for phenyl substituents by the calculated values of R in Table 30.1 [28]. 

Precise isotope ratios are also necessary in studies of kinetic isotope-elfects, isotope-dilution studies, and dating work. 

This study has important lessons for enzyme kinetic analysis. The use of pH variation and examination of isotope elfects can be a powerful combination to explore the chemistry of enzyme-catalyzed reactions and to dissect the contributions of individual reaction steps to the net steady-state turnover (27). Examination of the effects of pH on each step of the reaction pathway could resolve the contributions of ionizable groups toward ground-state binding energy and transition-state stabilization. The use of isotope effects by transient-state kinetic methods is more limited than in the steady state due to the errors involved in comparing two rate measurements. In the steady state, the ratio method has allowed isotope effects of less than 1% to be measured accurately (8a, 58). By transient-state kinetics, one would require at least a 10-20% change in rate to demonstrate a convincing difference between two rate measurements in most instances. 

It has been proposed that the isotope elFects for the P450-catalyzed oxidations of hydrocarbons and alkylamines are similar to those observed in the reactions of the same substrates with the tert-butoxyl radical The finding that the measured kinetic isotope effects for the hydrogen abstraction from benzylic methyl groups fall on the same line as those for the iV-demethylation of... 

The kinetic data together with isotope exchange and solvent isotope elfect data are consistent with a mechanism involving non-interconverting cis and trans allylic carbanion intermediates, with partially intramolecular proton transfer,... 

However, niacin does not inhibit the selective uptake of HDL cholesteryl esters into the cells (Kamanna and Kashyap 2008). This combination of elfects could raise HDL concentration, enhancing the ability of HDL to shuttle cholesterol from peripheral tissues to the liver. Apolipoprotein A-I (apoA-I) is the major protein associated with HDL. In HepG2 cells, niacin did not increase transcription or synthesis of apoA-I (Kamanna and Kashyap 2008). However, a stable isotope kinetic study in humans showed increased production of apoA-I following the administration of niacin (Lamon-Fava et al. 2008). 

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