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Titolo:
Slow-binding inhibition of the aminopeptidase from Aeromonas proteolytica by peptide thiols: Synthesis and spectroscopic characterization
Autore:
Huntington, KM; Bienvenue, DL; Wei, YM; Bennett, B; Holz, RC; Pei, DH;
Indirizzi:
Ohio State Univ, Dept Chem, Columbus, OH 43210 USA Ohio State Univ Columbus OH USA 43210 , Dept Chem, Columbus, OH 43210 USA Ohio State Univ, Ohio State Biochem Program, Columbus, OH 43210 USA Ohio State Univ Columbus OH USA 43210 hem Program, Columbus, OH 43210 USA Utah State Univ, Dept Chem & Biochem, Logan, UT 84322 USA Utah State UnivLogan UT USA 84322 pt Chem & Biochem, Logan, UT 84322 USA
Titolo Testata:
BIOCHEMISTRY
fascicolo: 47, volume: 38, anno: 1999,
pagine: 15587 - 15596
SICI:
0006-2960(19991123)38:47<15587:SIOTAF>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
LENS LEUCINE AMINOPEPTIDASE; TRANSITION-STATE-ANALOG; ANGIOTENSIN-CONVERTING ENZYME; L-LEUCINEPHOSPHONIC ACID; METHIONINE AMINOPEPTIDASE; CATALYTIC MECHANISM; CRYSTAL-STRUCTURE; BETA-LACTAMASE; CELL INVASION; ACTIVE-SITE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
57
Recensione:
Indirizzi per estratti:
Indirizzo: Holz, RC Ohio State Univ, Dept Chem, 100 W 18th Ave, Columbus, OH 43210 USA Ohio State Univ 100 W 18th Ave Columbus OH USA 43210 OH 43210 USA
Citazione:
K.M. Huntington et al., "Slow-binding inhibition of the aminopeptidase from Aeromonas proteolytica by peptide thiols: Synthesis and spectroscopic characterization", BIOCHEM, 38(47), 1999, pp. 15587-15596

Abstract

Peptide-derived thiols of the general structure N-mercaptoacyl-leucyl-p-nitroanilide (la - c) were synthesized and found to be potent, slow-binding inhibitors of the aminopeptidase from Aeromonas proteolytica (AAP). The overall potencies (K-I*) of these inhibitors against AAP range from 2.5 to 57 nM exceeding that of the natural product bestatin and approaching that of amastatin. The corresponding alcohols (2a-b) are simple competitive inhibitors of much lower potencies (K-I = 23 and 360 mu M) These data suggest that the free thiols are involved in the formation of the E . I and E . I* complexes, presumably serving as a metal ligand. To investigate the nature of theinteraction of the thiol-based inhibitors with the dinuclear active site of AAP, we have recorded electronic absorption and EPR spectra of Co(II)Co(II)-, Co(II)Zn(II)-, and Zn(II)Co(II)-AAP in the presence of the strongest binding inhibitor, Ic. Both [CoZn (AAP)] and [ZnCo(AAP)I, in the presence ofIc, exhibited an absorption band centered at 320 nm characteristic of an S--> Co(LI) ligand-metal charge-transfer band. In addition, absorption spectra recorded between 400 and 700 nm showed changes characteristic of Ic interacting with each active-site metal ion. EPR spectra recorded at high temperature (19 K) and low power (2.5 mW) indicated that in a given enzyme molecule, Ic interacts weakly with one of the metal ions in the dinuclear site and that the crystallographically identified mu-OH(H) bridge, which has been shown to mediate electronic interaction of the Co(II) ions, is likely broken upon Ic binding. EPR spectra of [CoCo(AAP)]-1c, [ZnCo(AAP)]-1c, and [CoZn(AAP)]-1c were also recorded at lower temperature (3.5-4.0 K) and high microwave power (50-553 mW). The observed signals were unusual and appeared to contain, in addition to the incompletely saturated contributions from thesignals characterized at 19 K, a very sharp feature at g(eff) approximate to 6.8 that is characteristic of thiolate-Co(II) interactions. These data suggest that the thiolate moiety can bind to either of the metal ions in thedinuclear active site of AAP but does not bridge the dinuclear cluster. Compounds la-e are readily accessible by synthesis and thus provide a novel class of potent aminopeptidase inhibitors.

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Documento generato il 01/12/20 alle ore 19:44:37