A minimalist approach to understanding the efficiency of mononuclear Zn(ii) complexes as catalysts of cleavage of an RNA analog

Abstract

Mononuclear complexes between Zn(2+) and the following four macrocycles were prepared: 1,4,7,10-tetraazacyclododecane (1), 1-oxa-4,7,10-triazacyclododecane (2), 1,5,9-triazacyclododecane (3) and 1-hydroxyethyl-1,4,7-triazacyclononane (4). The pH rate profiles of values of the observed second-order rate constant log (k(Zn))(app) for Zn(X)(OH(2))-catalyzed cleavage (X = 1, 2, 3 and 4) of 2-hydroxypropyl-4-nitrophenyl phosphate (HpPNP) show downward breaks centered at the pK(a) for ionization of the respective zinc bound water. At low pH, where the rate acceleration for the catalyzed reaction is largest, the stabilizing interaction between the catalyst and the bound transition state is 5.7, 7.4, 7.4 and 5.9 kcal mol(-1) for the reactions catalyzed by Zn(1)(OH(2)), Zn(2)(OH(2)), Zn(3)(OH(2)) and Zn(4)(OH(2)), respectively. The interactions between the metal cation and the macrocycle cause either a modest increase or reduction in transition state stabilization compared with 6.6 kcal mol(-1) stabilization for catalysis by Zn(OH(2))(6). The best Zn(II)-macrocycle catalysts are those for which the interactions between the metal ion and macrocycle are the weakest. Inhibition studies show that each of the four catalysts form complexes with phosphate and oxalate dianions with a much higher affinity than diethyl phosphate monoanion, consistent with stronger interaction of the catalysts with the transition state dianion compared with the substrate monoanion HpPNP. The pH-dependence of methyl phosphate inhibition of Zn(2) catalyzed cleavage of HpPNP shows that only the Zn(2)(OH(2)) species binds the inhibitor. This result is consistent with a mechanism that has Zn(2)(OH(2)) as the active catalytic species.

Mononuclear and dinuclear mechanisms for catalysis of phosphodiester cleavage by alkaline earth metal ions in aqueous solution

“…These values correspond to 90 and 900-fold catalysis and DDG à of 12 kJ/mol for the first Ca 2+ ion, but only 6 kJ/mol for the second Ca 2+ ion ( Table 1). The smaller catalytic contribution of the second ion is consistent with other systems where mononuclear and dinuclear mechanisms have been compared, including cleavage of the RNA models by Zn 2+ complexes [12][13][14] and restriction endonucleases [36,37]. Importantly, the basic conclusion that Ca 2+ catalyzes T5PNP hydrolysis by two parallel mechanisms remains valid regardless of the values of K Ca1-T , k OHCa1 , and k OHCa2 .…”

“…Much of the research examining these mechanisms using model systems has focused on transition and lanthanide metal ions [5][6][7][8][9][10][11][12][13][14][15][16][17]. Although Mg 2+ is one of the most common metal ions used by biological systems, there is relatively less work related to catalysis by alkaline earth metal ions [18][19][20][21].…”

Phosphodiester hydrolysis and specific DNA binding and cleavage promoted by guanidinium-functionalized zinc complexes

“…Nature has selected an impressive array of metalloenzymes, often with one or more coordinated metal ions at their active sites that catalyze efficiently the hydrolytic cleavage of such bonds to sustain life [5][6][7][8][9][10]. Many zinc complexes are known to be synthetic hydrolases towards the phosphodiester cleavage of DNA [5,6,[11][12][13][14][15][16][17][18][19][20][21][22][23][24]. Among the various model complexes, the Zn(II) complexes incorporating functional groups, such as the carboxyl groups of aspartate residue, or the guanidinium/amino groups of arginine residue, or many other organic groups belonging to the amino acid residue side chains, have been shown to hydrolyze phosphodiester at reasonably faster rates [18,[20][21][22]24].…”

Zinc(II) tweezers containing artificial peptides mimicking the active site of phosphotriesterase: The catalyzed hydrolysis of the toxic organophosphate parathion

“…Several studies have been devoted to elucidate the effect of the ligand structure in modulating the reactivity of the metal center [33][34][35][36] but it is quite clear that the desired acceleration cannot be reached with simple mononuclear complexes [37][38][39][40][41][42][43][44].…”