Enzyme action, discovery of the mechanisms

Enzyme action, discovery of the mechanisms of, 1947-1963, 21, 1 Equilibrating systems, isotope effects on nmr spectra of, 23, 63 Equilibrium constants, N.M.R. measurements of, as a function of temperature, 3,187 Ester hydrolysis, general base and nucleophilic catalysis, 5, 237 Exchange reactions, hydrogen isotope, of organic compounds in liquid ammonia, 1, 156... 

Another of Conant s students was Frank Westheimer (b. 1912), who, after postdoctoral work with Hammett at Columbia, held a post at the University of Chicago (1936-1954) and then returned to Harvard. Westheimer worked in several areas of physical organic chemistry and engaged in other chemistry-based activities, as revealed in an interview conducted in 1995 by Istvan Hargittai.233 For much of his career, Westheimer was essentially a physical organic chemist working in biochemistry and he has himself written reflectively on the discovery of the mechanisms of enzyme action over the period 1947-1963234 and on the application of physical organic chemistry to biochemical problems.235 Westheimer has also contributed, as Tetrahedron Perspective Number 4, an article on Coincidences, decarboxylation, and electrostatic effects , which, he writes, ...allows me to review some of my past .236... 

Directive effects in aromatic substitution, a quantitative treatment of, 1, 35 Directive effects in gas-phase radical addition reactions, 16, 51 Discovery of the mechanisms of enzyme action, 1947-1963, 21, 1 Displacement reactions, gas-phase nucleophilic, 21, 197... 

The discovery of the antiulcer activity of H2 antihistamine antagonists has revolutionized the treatment of that disease. A benzimidazole. Omeprazole (55), inhibits gastric secretion and subsequent ulcer formation by a quite different mechanism. Studies at the molecular level suggest that this compound inhibits K /H dependent ATPase and consequently shuts down the proton pumping action of this enzyme system. 

In 1985, it was reported by Hsiang et al. [43] that the cytotoxic activity of 20-(S)-camptothecin (CPT III) was attributed to a novel mechanism of action involving the nuclear enzyme topo I, and this discovery of unique mechanism of action revived the interest in CPT and its analogues as anticancer agents. CPT stabilizes the covalent, reversible topo I-DNA complex leading to the inhibition of DNA synthesis in mammalian cells and interferes with the topo I breakage-reunion reaction [44]. Clinical trials and structure-activity relationships have demonstrated the requirement of the a-hydroxy group, the... 

Another early success in biomimetic chemistry concerns reactions promoted by thiamin. In 1943, more than 35 years ago, Ukai, Tanaka, and Dokowa (12) reported that thiamin will catalyze a benzoin-type condensation of acetaldehyde to yield acetoin. This reaction parallels a similar enzymic reaction where pyruvate is decarboxylated to yield acetoin and acetolactic acid. Although the yields of the nonenzymic process are low, it is clearly a biomimetic process further investigation by Breslow, stimulated by the early discovery of Ugai et al., led to an understanding of the mechanism of action of thiamin as a coenzyme. 

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