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Titolo:
CORRELATION OF THE MOLECULAR ELECTROSTATIC POTENTIAL SURFACE OF AN ENZYMATIC TRANSITION-STATE WITH NOVEL TRANSITION-STATE INHIBITORS
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: 38, volume: 32, anno: 1993,
pagine: 9917 - 9925
SICI:
0006-2960(1993)32:38<9917:COTMEP>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
AMP NUCLEOSIDASE; CRITHIDIA-FASCICULATA; GLUCOSIDASE; SPECIFICITY; HYDROLASE; CATALYSIS; ANALOGS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
33
Recensione:
Indirizzi per estratti:
Citazione:
B.A. Horenstein e V.L. Schramm, "CORRELATION OF THE MOLECULAR ELECTROSTATIC POTENTIAL SURFACE OF AN ENZYMATIC TRANSITION-STATE WITH NOVEL TRANSITION-STATE INHIBITORS", Biochemistry, 32(38), 1993, pp. 9917-9925

Abstract

The transition state stabilized by nucleoside hydrolase from Crithidia fasciculata is characterized by nearly complete glycosidic bond cleavage and oxycarbonium character in the ribosyl group [Horenstein, B. A., Parkin, D. W., Estupinan, B., & Schramm, V. L. (1991) Biochemistry 30, 10788-10795]. The electrostatic potential surface of the transition state provides detailed information which should be useful in the design of transition-state analogues [Horenstein, B. A., & Schramm, V. L. (1993) Biochemistry 32, 7089-7097]. The electrostatic potential surface of inosine at the transition state contains a distributed positivecharge resulting from the oxycarbonium ion character of the ribosyl ring. The ribosyl ring pucker is 3'-exo as a result of the near sp2 hybridization at C1' of the ribose ring. A series of transition-state analogues have been synthesized which in corporate single or combined features of the transition state. Each feature of the transition state was analyzed for its contribution to binding energy. Kinetic inhibition constants correlate with the similarity of the inhibitor to the experimentally determined transition-state structure. Dissociation constantsfor the substrate and products of the reaction of inosine, hypoxanthine, and ribose are 380, 6200, and 700 muM, respectively. A transition-state analogue was synthesized which contains the required hydroxyl groups of the ribose ring, the positive charge feature of the oxycarbonium ion, and a hydrophobic mimic of the purine ring. The inhibitor 1(S)-phenyl-1,4-dideoxy-1,4-iminoribitol acts as a competitive inhibitor with respect to inosine with a dissociation constant of 0.17 muM. In addition, the inhibitor exhibits slow-onset inhibition which provides a final equilibrium dissociation constant of approximately 0.03 muM. Theaffinity of inhibitor binding correlates to the match between the electrostatic potential surfaces of the inhibitors and the transition states but less well to the geometric similarity. The results establish that an enzymatic transition state characterized by a family of kineticisotope effects, bond vibrational analysis, and molecular electrostatic potentials facilitates the design of transition-state inhibitors.

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Documento generato il 18/09/20 alle ore 17:04:33