Nv. Kaminskaia et al., Reactivity of mu-hydroxodizinc(II) centers in enzymatic catalysis through model studies, INORG CHEM, 39(15), 2000, pp. 3365-3373
The stable dinuclear complex [Zn-2(BPAN) (mu-OH)(mu-O2PPh2)] (ClO4)(2), whe
re BPAN = 2,7-bis [2-(2-pyridylethyl)-aminomethyl]-1,8-naphthyridine, was c
hosen as a model to investigate the reactivity of (mu-hydroxo)dizinc(II) ce
nters in metallohydrolases. Two reactions, the hydrolysis of phosphodiester
s and the hydrolysis of beta-lactams, were studied. These two processes are
catalyzed in vivo by zinc(II)-containing enzymes: P1 nucleases and beta-la
ctamases, respectively. The former catalyzes the hydrolysis of single-stran
ded DNA and RNA. beta-Lactamases, expressed in many types of pathogenic bac
teria, are responsible for the hydrolytic degradation of beta-lactam antibi
otic drugs. In the first step of phosphodiester hydrolysis promoted by the
dinuclear model complex, the substrate replaces the bridging diphenylphosph
inate. 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 tha
na mononuclear analogue, Zn(bpta)(OTf)(2), where bpta = N,N-bis- (2-pyridyl
methyl)-tert-butylamine. Hydrolysis of nitrocefin, a beta-lactam antibiotic
analogue, catalyzed by [Zn-2(BPAN)(mu-OH)(mu-O2PPh2)](ClO4)(2) involves mo
nodentate coordination of the substrate via its carboxylate group, followed
by nucleophilic attack of the zinc(II)-bound terminal hydroxide at the bet
a-lactam carbonyl carbon atom. Collapse of the tetrahedral intermediate res
ults in product formation. Mononuclear complexes Zn(cyclen)-(NO3)(2) and Zn
(bpta)(NO3)(2), where cyclen 1,4,7,10-tetraazacyclododecane, are as reactiv
e in the beta-lactam hydrolysis as the dinuclear complex. Kinetic and mecha
nistic studies of the phosphodiester and beta-lactam hydrolyses indicate th
at the bridging hydroxide in [Zn-2(BPAN)(mu-OH)(mu-O2PPh2)] (ClO4)(2) is no
t very reactive, despite its low pK, value. This low reactivity presumably
arises from the two factors. First, the bridging hydroxide and coordinated
substrate in [Zn-2(BPAN)(mu-OH)(substrate)](2+) are not aligned properly to
favor nucleophilic attack. Second, the nucleophilicity of the bridging hyd
roxide is diminished because it is simultaneously bound to the two zinc(II)
ions.