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Titolo:
CONSCRIPTING THE ACTIVE-SITE ZINC ION IN CARBOXYPEPTIDASE-A IN INACTIVATION CHEMISTRY BY A NEW-TYPE OF IRREVERSIBLE ENZYME INACTIVATOR
Autore:
TANAKA Y; GRAPSAS I; DAKOJI S; CHO YJ; MOBASHERY S;
Indirizzi:
WAYNE STATE UNIV,DEPT CHEM DETROIT MI 48202 WAYNE STATE UNIV,DEPT CHEM DETROIT MI 48202
Titolo Testata:
Journal of the American Chemical Society
fascicolo: 17, volume: 116, anno: 1994,
pagine: 7475 - 7480
SICI:
0002-7863(1994)116:17<7475:CTAZII>2.0.ZU;2-C
Fonte:
ISI
Lingua:
ENG
Soggetto:
MECHANISM-BASED INACTIVATORS; ANGIOTENSIN-CONVERTING ENZYME; RENAL DIPEPTIDASE; FORMULA )(ETA-5-C5H5)RE(NO)(PPH3)(IR)>+BF4; COORDINATION CHEMISTRY; CATALYZED ENOLIZATION; HALIDE-COMPLEXES; IODIDE COMPLEXES; PH-DEPENDENCE; STABLE ALKYL;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
69
Recensione:
Indirizzi per estratti:
Citazione:
Y. Tanaka et al., "CONSCRIPTING THE ACTIVE-SITE ZINC ION IN CARBOXYPEPTIDASE-A IN INACTIVATION CHEMISTRY BY A NEW-TYPE OF IRREVERSIBLE ENZYME INACTIVATOR", Journal of the American Chemical Society, 116(17), 1994, pp. 7475-7480

Abstract

A new strategy for irreversible inactivation of the metalloenzyme carboxypeptidase A (CPA) involving a proposed activation of a carbon-iodide bond in an inactivator by the active-site zinc ion toward nucleophilic substitution is described. 2-Benzyl-3-iodopropanoic acid (compound1) was designed to bind the active site of CPA. An energy-minimized complex of 1 in the active site of CPA reveals that the iodo moiety comes within the coordination sphere of the zinc ion. Such metal coordination was expected to facilitate the departure of the halide in an S(N)2-type reaction by the side-chain functions of either Glu-270 or Tyr-248. Compound 1 was shown-to inactivate CPA in a time-dependent manner,a process which was active-site directed and irreversible; a rate enhancement of approximately 10(8)-10(9)-fold is estimated for the inactivation chemistry by 1 over model metal-activated S(N)2 type reactions.2-Benzyl-4-iodobutanoic acid (compound 6), an analog of 1 with an extended structure by one methylene unit, was shown to serve solely as a poor competitive inhibitor for CPA (K-i = 0.41 +/- 0.07 mM) but not asan irreversible inactivator; a discussion of the kinetic behavior by the two compounds is provided. The results reported herein hold the promise of a novel chemistry for selective inactivation of metalloenzymes.

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Documento generato il 30/11/20 alle ore 00:40:15