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Titolo:
ELECTRONIC NATURE OF THE TRANSITION-STATE FOR NUCLEOSIDE HYDROLASE - A BLUEPRINT FOR INHIBITOR DESIGN
Autore:
HORENSTEIN BA; SCHRAMM VL;
Indirizzi:
YESHIVA UNIV ALBERT EINSTEIN COLL MED,DEPT BIOCHEM,1300 MORRIS PK AVEBRONX NY 10461 YESHIVA UNIV ALBERT EINSTEIN COLL MED,DEPT BIOCHEM,1300 MORRIS PK AVEBRONX NY 10461
Titolo Testata:
Biochemistry
fascicolo: 28, volume: 32, anno: 1993,
pagine: 7089 - 7097
SICI:
0006-2960(1993)32:28<7089:ENOTTF>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
NICOTINAMIDE GLYCOSYL BOND; AMP NUCLEOSIDASE; CRITHIDIA-FASCICULATA; ENZYME CATALYSIS; AQUEOUS-SOLUTION; MECHANISM; CHEMISTRY; PURIFICATION; SPECIFICITY; NUCLEOTIDE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
52
Recensione:
Indirizzi per estratti:
Citazione:
B.A. Horenstein e V.L. Schramm, "ELECTRONIC NATURE OF THE TRANSITION-STATE FOR NUCLEOSIDE HYDROLASE - A BLUEPRINT FOR INHIBITOR DESIGN", Biochemistry, 32(28), 1993, pp. 7089-7097

Abstract

A new approach to understanding transition-state structure is presented which involves the sequential application of experimental and computational methods. A family of experimentally determined kinetic isotope effects is fit simultaneously in a vibrational analysis to provide ageometric model of the transition state. The electrostatic potential surface of the geometric model is defined by molecular orbital calculations to detail the electronic nature of the transition state. The method provides both geometric and charge information for the enzyme-stabilized transition state. Electrostatic potential surface calculations were applied to the N-glycohydrolase reaction catalyzed by nucleoside hydrolase from the trypanosome Crithidia fasciculata. A geometric model of the transition-state structure for the enzymatic hydrolysis of inosine by nucleoside hydrolase has been established by the analysis of a family of kinetic isotope effects [Horenstein, B.A., Parkin, D.W., Estupinan, B., & Schramm, V.L. (1991) Biochemistry 30, 10788]. The transition state has substantial oxycarbonium ion character, but the results of electrostatic potential calculations indicate that the transition-state charge is distributed over the ribosyl ring rather than existing as a localized C+-O <-) C=O+ resonance pair. The electrostatic potential surfaces of the substrate and enzyme-bound products differ considerably from that of the transition state. At the transition state both hypoxanthine and ribose demonstrate regions of positive charge. The positive charge on the ribosyl oxycarbonium ion is moderated by association with an enzyme-directed water nucleophile. The enzyme-bound products contain adjacent areas of negative charge. The electrostatic potential surfaces provide novel insights into transition-state structure and the forces causing release of products. The reaction coordinate for nucleoside hydrolase can now be defined in terms of the molecular electrostatic potential surface of inosine as it traverses the reaction coordinate. Ribonolactone and 1,4-dideoxy-1,4-iminoribitol contain several geometric features of the transition state, respectively, and aresuperior inhibitors compared to substrate, substrate analogues, or products.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 18/09/20 alle ore 17:12:36