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Mimicking Enzymes: The Quest for Powerful Catalysts from Simple Molecules to Nanozymes
ACS Catalysis ( IF 12.9 ) Pub Date : 2021-09-05 , DOI: 10.1021/acscatal.1c01219 Yanchao Lyu 1 , Paolo Scrimin 1
ACS Catalysis ( IF 12.9 ) Pub Date : 2021-09-05 , DOI: 10.1021/acscatal.1c01219 Yanchao Lyu 1 , Paolo Scrimin 1
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Enzymes bind, and thus stabilize selectively, the transition state of the reaction they catalyze. The intuition of Fischer, who introduced the lock and key principle,(8) proved unsuitable to explain enzyme catalysis. Pauling was the first(9) in 1948 who suggested enzymes’ trick was to stabilize the transition state of a reaction rather than the ground state.(10) More recently Jencks has authoritatively supported that suggestion.(11,12) Transition-state binding equates to a lowered reaction barrier and thus to an increased turnover rate in comparison to the uncatalyzed reaction in solution. The binding of the reactants in the catalytic site transforms an intermolecular reaction into a (pseudo) intramolecular one. As noted by Kirby,(12b) “The only simple reactions that can rival their enzyme-catalyzed counterparts in rate are intramolecular reactions such as cyclizations, and specifically intramolecular nucleophilic reactions.” This aspect is so important that several enzymes are believed to use the trick of covalently binding the transition state.(13) Functional groups are present in the catalytic site to transfer protons, stabilize charges, coordinate metal ions, and act as nucleophiles/electrophiles. They must be properly oriented and located to optimize their interaction with the substrate in its transformation into the transition state. This led to the introduction of concepts such as the “near attack conformation”(14) and the “spatiotemporal theory”,(15) the “entatic state”(16) for metal complexes. Furthermore, and particularly important, they must operate in a concerted way, leading to cooperativity.(17) The catalytic site of an enzyme differs from the bulk solution in terms of solvation properties(18) and local pH(19) in relation to the functional groups present (polar/apolar, anionic/cationic). This may affect, for instance, the nucleophilicity and the pKa of the functional groups involved. Figure 1. Structure of enzyme mimetic catalysts whose reactivity is reported in Table 1: (A) β-cyclodextrin with ferrocenyl derivative; (B) macrocyclic host with a complexed protonated alanine p-nitrophenyl ester substrate; (C) rigid receptor for methanolysis; (D) dendrimers; (E) hapten used for the development of catalytic antibodies for ester hydrolysis; (F) catalytic site of an imprinted polymer with transition state analogue for carbamate hydrolysis; (G) functional peptide for ester hydrolysis; (H) peptide-functionalized gold nanoparticle for ester hydrolysis. Refer to Figure 1 for the structure of catalysts and substrates. The indications i–iv refer to the four common features present in enzymes that derive from the study of natural enzymes and enzyme models and are at the basis of their activity discussed in the Introduction. The rate acceleration exerted by the catalyst that gives an immediate evaluation of how much faster the catalyzed reaction proceeds in comparison to the uncatalyzed catalyst (i.e., the pseudo-first-order rate constant in the absence of catalyst). kcat is the first-order rate constant that evaluates the rate of transformation of the substrate at saturation of the catalyst, and KM is the reciprocal of the affinity constant of the substrate for the catalyst (assuming a binding equilibrium faster than the rate of product formation). The ratio has the dimensions of a second-order rate constant and is a measure of how efficiently the catalyst converts the substrate into products under subsaturation conditions, also taking into consideration the efficiency of its binding; Second-order rate constant in the absence of binding. Expressed in units of concentration and, quoting its definition, “represents the lower limit of the enzyme’s affinity for the altered substrate in the transition state”.(29) The background reaction is immeasurably slow under the experimental conditions; Estimated from the turnover frequency; the affinity of the catalyst for the substrate is low (0.79 M–1). Figure 2. Evolution of the efficiency of simple synthetic metallocatalysts for the cleavage of the RNA model substrate HPNP. The red and blue arrows are meant to guide the eye in following the progressive improvement of the catalysts. In red: (a) from one to two metals; (b) the need for structure organization; (c) solvent effect. In blue: (a) the role of proton donors; (b) from one to two metal ions; (c) merging (a) and (b); (d) solvent effect. References: 1 and 2, ref (47); 3a, ref (48); 3b, ref (49); 3c, ref (46); 4, ref (50); 5 and 6, ref (51); 7, ref (52). Figure 3. Multivalent nanocatalysts for the cleavage of HPNP (from 8 to 10) and plasmid DNA (11 and 12), taking advantage of cooperativity, medium control, and (for 11 and 12) very efficient binding to the substrate leading to their being dubbed nanozymes. References: 8, ref (55); 9, ref (56); 10, ref (28); 11, ref (61); 12, ref (59). Figure 4. Comparison between the proposed catalytic mechanism for the cleavage of DNA by nanozyme 12 (left, ref (59)) and type IA and II topoisomerases (right) as suggested by Berger (ref (45b)). The enzyme is a dinuclear one, but only one metal ion was proposed as catalytically active. The red arrows denote the Zn(II) ions and the blue arrows the guanidinium groups, while the curly arrows indicate the attack of the nucleophile (serine or tyrosine) to the phosphorus atom of the phosphate. The authors are indebted to Professors Leonard J. Prins and Fabrizio Mancin for fruitful and stimulating discussions during the writing of this contribution. The support of the China Scholarship Council by a fellowship to Y.L. is gratefully acknowledged. This article references 81 other publications.
更新日期：2021-09-17
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