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Radioactivity and Radiotracers
Published in Graham Lappin, Simon Temple, Radiotracers in Drug Development, 2006
Let us assume that the reactants X and Y are organic compounds and contain only a light isotope (L) (equation 2.12). Now let us assume that the light isotope in reactant X is replaced with a heavy isotope (H) (equation 2.13). Due to the kinetic isotope effect, the rate of the reaction represented by equation 2.13 will be somewhat slower than that represented in equation 2.12. The magnitude of the kinetic isotope effect is simply defined as the ratio of the rate constants based upon the light (kL) and heavy (kH) isotopes.
The Reaction Mechanism
Published in D. B. Keech, J. C. Wallace, Pyruvate Carboxylase, 2018
This explanation for the variable stoichiometry is supported by several lines of evidence. For example, during their nuclear magnetic resonance (NMR) studies, Mildvan and Scrutton 567 showed that, in the case of the chicken liver pyruvate carboxylase, pyruvate bound to the enzyme in a rapid equilibrium manner; they showed that pyruvate moved into and out of the second subsite at rates which were two orders of magnitude faster than the rate of the overall reaction. Therefore, if the binding of pyruvate is the signal for the carboxybiotin to move into the second subsite, there is no guarantee that it will still be there when the carboxybiotin arrives. Furthermore, when studying the rate of oxaloacetate decarboxylation, i.e., the reversal of Equation 3, Easterbrook-Smith et al.251 found that in the presence of nonsaturating levels of pyruvate there was a very significant rate of decarboxylation. If, however, pyruvate was removed from the system using lactate dehydrogenase and NADH, the rate of decarboxylation was negligible, again suggesting that pyruvate was a necessary catalyst in labilizing the carboxybiotin. Finally, the above explanation is also consistent with the conclusion of Cheung and Walsh,182 who studied the kinetic isotope effect of tritiated pyruvate on both the catalytic step involving the carboxylation of pyruvate and the overall reaction. As a result of their studies, one of the conclusions these authors made was that "after the pyruvate molecule binds to the enzyme, it is only about 50% committed to catalysis, i.e., it will dissociate without reacting one out of two times it binds."
Insights into the Progression of Labile Hb A1c to Stable Hb A1c via a Mechanistic Assessment of 2,3-Bisphosphoglycerate Facilitation of the Slow Nonenzymatic Glycation Process
Published in Hemoglobin, 2019
Christina R. Mottishaw, Stephanie Becker, Brandy Smith, Gentry Titus, R.W. Holman, Kenneth J. Rodnick
Lowrey et al. [22] suggested and Gil et al. [24] demonstrated that the formation of stable Hb A1c structure 6 from labile Hb A1c structure 3 is largely (or entirely) irreversible and slow, constituting the rate-determining step of NEG for Hb A in the presence of 2,3-BPG. Smith et al. [12], extending from their data, posited that the rate of conversion from the conjugate acid of the Schiff base (labile Hb A1c, structure 3) to stable Hb A1c (structure 6, the Amadori product; Figure 1, mechanistic pathway I) increases under the influence of nearby 2,3-BPG. Gil et al. [24], using kinetic isotope effect (KIE) analysis, definitively demonstrated that the mechanistic step that determines the rate of stable Hb A1c formation in the presence of 2,3-BPG is the abstraction of the C2-proton on structure 3, by a base (Figure 1, mechanistic pathway I, with the abstraction of the proton that is rendered in blue). The KIE method of Gil et al. [24] did not, however, enable the identification of the specific base (or bases) involved. Our intent is to discern what the base(s) is/are that deprotonate the C2 proton on labile Hb A1c structure 3 in the progression towards stable Hb A1c structure 6 and to determine whether other acid/base and/or nucleophile/electrophile reactions can occur that alter the rate of progression from structures 3 to 6. The intent is to elucidate why stable Hb A1c formation is so slow (on the order of weeks) and to better understand the structural/mechanistic chemistry associated with the clinical assay methods utilized to eliminate labile Hb A1c structure 3 prior to the measurement of stable Hb A1c structure 6.
Drug metabolic stability in early drug discovery to develop potential lead compounds
Published in Drug Metabolism Reviews, 2021
Siva Nageswara Rao Gajula, Nimisha Nadimpalli, Rajesh Sonti
The incorporation of deuterium may not resolve the metabolic stability issue for every drug molecule. The drug’s metabolic fate and enzymology can be explored by a sensible choice of both the drug molecule and the deuteration site (Cargnin et al. 2019). Therefore, <10% of the FDA-approved drugs are amenable to deuteration because of their chemical structure or insignificant kinetic isotope effect in their metabolism. In addition, the deuteration of a drug may cause potential metabolic switches that lead to the drug’s biotransformation via another metabolic pathway (Cargnin et al. 2019).
A patent review of pharmaceutical and therapeutic applications of oxadiazole derivatives for the treatment of chronic diseases (2013–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Abbas Hassan, Abid Hussain Khan, Faiza Saleem, Haseen Ahmad, Khalid Mohammed Khan
The marketed drug ozanimod (RCP-1063) is an S1P receptor agonist and is used for the treatment of multiple sclerosis and ulcerative colitis as an immunomodulator. Ozanimod has also shown promise in the treatment of transplant rejection, adult respiratory syndrome, influenza, and Crohn’s disease. Various enzymes, such as the cytochrome P450 enzymes (CYPs), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases convert foreign substances such as any drug, to more polar metabolites for easy renal excretion. Such metabolic reactions often consist of the oxidation of a carbon-hydrogen (C-H) bond to a carbon-oxygen (C-O) bond. The resultant metabolites may be stable or unstable under physiological conditions and can have substantially different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles relative to the parent compounds. For most drugs, such oxidations are generally rapid and ultimately lead to the administration of multiple or high daily doses. The C-H bond strength is directly proportional to the absolute value of the ground-state vibrational energy of the bond, which depends on the mass of the atoms that form the bond. An increase in the mass of one or both atoms making the bond increases the bond strength. Since deuterium (2H) has twice the mass of protium, a C-2H bond is stronger than the corresponding C-H. If a C-H bond is broken during a rate-determining step in a chemical reaction, then substituting a 2H for that 1H will cause a decrease in the reaction rate. This phenomenon is known as the Kinetic Isotope Effect. It is important to identify the metabolites formed during the metabolism of the drug, which can be identified from isotopic labeling and their rate of formation relative to heavy isotope will give information about which bond is indeed oxidized in rate-limiting steps [106,107].