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Titolo:
Reactivity of mu-hydroxodizinc(II) centers in enzymatic catalysis through model studies
Autore:
Kaminskaia, NV; He, C; Lippard, SJ;
Indirizzi:
MIT, Dept Chem, Cambridge, MA 02139 USA MIT Cambridge MA USA 02139MIT, Dept Chem, Cambridge, MA 02139 USA
Titolo Testata:
INORGANIC CHEMISTRY
fascicolo: 15, volume: 39, anno: 2000,
pagine: 3365 - 3373
SICI:
0020-1669(20000724)39:15<3365:ROMCIE>2.0.ZU;2-Z
Fonte:
ISI
Lingua:
ENG
Soggetto:
METALLO-BETA-LACTAMASE; PHOSPHATE DIESTER; CRYSTAL-STRUCTURE; BACTEROIDES-FRAGILIS; BACILLUS-CEREUS; BIOCHEMICAL-CHARACTERIZATION; AEROMONAS-PROTEOLYTICA; ANGSTROM RESOLUTION; RNA HYDROLYSIS; ZINC ENZYMES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Physical, Chemical & Earth Sciences
Citazioni:
51
Recensione:
Indirizzi per estratti:
Indirizzo: Lippard, SJ MIT, Dept Chem, Cambridge, MA 02139 USA MIT Cambridge MA USA 02139 Dept Chem, Cambridge, MA 02139 USA
Citazione:
N.V. Kaminskaia et al., "Reactivity of mu-hydroxodizinc(II) centers in enzymatic catalysis through model studies", INORG CHEM, 39(15), 2000, pp. 3365-3373

Abstract

The stable dinuclear complex [Zn-2(BPAN) (mu-OH)(mu-O2PPh2)] (ClO4)(2), where BPAN = 2,7-bis [2-(2-pyridylethyl)-aminomethyl]-1,8-naphthyridine, was chosen as a model to investigate the reactivity of (mu-hydroxo)dizinc(II) centers in metallohydrolases. Two reactions, the hydrolysis of phosphodiesters and the hydrolysis of beta-lactams, were studied. These two processes are catalyzed in vivo by zinc(II)-containing enzymes: P1 nucleases and beta-lactamases, respectively. The former catalyzes the hydrolysis of single-stranded DNA and RNA. beta-Lactamases, expressed in many types of pathogenic bacteria, are responsible for the hydrolytic degradation of beta-lactam antibiotic drugs. In the first step of phosphodiester hydrolysis promoted by thedinuclear model complex, the substrate replaces the bridging diphenylphosphinate. The bridging hydroxide serves as a general base to deprotonate water, which acts asa nucleophile in the ensuing hydrolysis. The dinuclear model complex is only 1.8 times more reactive in hydrolyzing phosphodiesters thana mononuclear analogue, Zn(bpta)(OTf)(2), where bpta = N,N-bis- (2-pyridylmethyl)-tert-butylamine. Hydrolysis of nitrocefin, a beta-lactam antibiotic analogue, catalyzed by [Zn-2(BPAN)(mu-OH)(mu-O2PPh2)](ClO4)(2) involves monodentate coordination of the substrate via its carboxylate group, followed by nucleophilic attack of the zinc(II)-bound terminal hydroxide at the beta-lactam carbonyl carbon atom. Collapse of the tetrahedral intermediate results in product formation. Mononuclear complexes Zn(cyclen)-(NO3)(2) and Zn(bpta)(NO3)(2), where cyclen 1,4,7,10-tetraazacyclododecane, are as reactive in the beta-lactam hydrolysis as the dinuclear complex. Kinetic and mechanistic studies of the phosphodiester and beta-lactam hydrolyses indicate that the bridging hydroxide in [Zn-2(BPAN)(mu-OH)(mu-O2PPh2)] (ClO4)(2) is not very reactive, despite its low pK, value. This low reactivity presumablyarises from the two factors. First, the bridging hydroxide and coordinatedsubstrate in [Zn-2(BPAN)(mu-OH)(substrate)](2+) are not aligned properly to favor nucleophilic attack. Second, the nucleophilicity of the bridging hydroxide is diminished because it is simultaneously bound to the two zinc(II) ions.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/03/20 alle ore 01:54:19