Probing Synergy between Two Catalytic Strategies in the Glycoside Hydrolase O-GlcNAcase Using Multiple Linear Free Energy Relationships

Human O-GlcNAcase plays an important role in regulating the post-translational modification of serine and threonine residues with β-O-linked N-acetylglucosamine monosaccharide unit (O-GlcNAc). The mechanism of O-GlcNAcase involves nucleophilic participation of the 2-acetamido group of the substrate to displace a glycosidically linked leaving group. The tolerance of this enzyme for variation in substrate structure has enabled us to characterize O-GlcNAcase transition states using several series of substrates to generate multiple simultaneous free-energy relationships. Patterns revealing changes in mechanism, transition state, and rate-determining step upon concomitant variation of both nucleophilic strength and leaving group abilities are observed. The observed changes in mechanism reflect the roles played by the enzymic general acid and the catalytic nucleophile. Significantly, these results illustrate how the enzyme synergistically harnesses both modes of catalysis; a feature that eludes many small molecule models of catalysis. These studies also suggest the kinetic significance of an oxocarbenium ion intermediate in the O-GlcNAcase-catalyzed hydrolysis of glucosaminides, probing the limits of what may be learned using nonatomistic investigations of enzymic transition-state structure and offering general insights into how the superfamily of retaining glycoside hydrolases act as efficient catalysts

Terrorisms war with America: a novel/ Piszkiewicz

x, 189 hal.: ill.; 24 cm

The challenge of the spaceship: Arthur C. Clarke and the history of the future, 1945-75

Arthur C. Clarke’s 1946 essay on ‘The Challenge of the Spaceship’ was one of the founding manifestoes of the Space Age, and helped to establish him as the West’s leading techno-prophet. Restating his ideas in subsequent factual and fictional works, Clarke successfully propagated the belief that man’s destiny lay in space and that the process was already underway. On the surface Clarke’s oeuvre offers a classic astrofuturist model of progress as technology-driven, but on closer examination it also incorporates a more pessimistic, historically based strand of philosophy, British rather than American. This essay traces the genesis of Clarke’s early work and the influence upon him of the historian Arnold J. Toynbee and the moral philosophers Olaf Stapledon and C.S. Lewis. Toynbee was essentially a Christian pessimist who believed that western civilization was on the way out; his long historical perspectives were an important source of inspiration for Clarke, leading him to a cyclical rather than a simply progressive model of history which contemplated both the beginning and the end of civilizations. The concerns of Stapledon and Lewis with grand narratives of decline and redemption were also influences on Clarke. All this needs to be understood in relation to both the European experience of World War I and to the coming of the atomic bomb, the latter a profound influence on Clarke’s generation. Such perspectives gave European astroculture a more modulated vision of the human future in space than the technologically based astrofuturism which dominated in the USA