Demetrius L
Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.
Protein Eng. 1995 Aug;8(8):791-800. doi: 10.1093/protein/8.8.791.
This paper codifies and rationalizes the large diversity in reaction rates and substrate specificity of enzymes in terms of a model which postulates that the kinetic properties of present-day enzymes are the consequence of the evolutionary force of mutation and selection acting on a class of primordial enzymes with poor catalytic activity and broad substrate specificity. Enzymes are classified in terms of their thermodynamic parameters, activation enthalpy delta H* and activation entropy delta S*, in their kinetically significant transition states as follows: type 1, delta H* > 0, delta S* < 0; type 2, delta H* < or = 0, delta S* < or = 0; type 3, delta H* > 0, delta S* > 0. We study the evolutionary dynamics of these three classes of enzymes subject to mutation, which acts at the level of the gene which codes for the enzyme and selection, which acts on the organism that contains the enzyme. Our model predicts the following evolutionary trends in the reaction rate and binding specificity for the three classes of molecules. In type 1 enzymes, evolution results in random, non-directional changes in the reaction rate and binding specificity. In type 2 and 3 enzymes, evolution results in a unidirectional increase in both the reaction rate and binding specificity. We exploit these results in order to codify the diversity in functional properties of present-day enzymes. Type 1 molecules will be described by intermediate reaction rates and broad substrate specificity. Type 2 enzymes will be characterized by diffusion-controlled rates and absolute substrate specificity. The type 3 catalysts can be further subdivided in terms of their activation enthalpy into two classes: type 3a (delta H* small) and type 3b (delta H* large). We show that type 3a will be represented by the same functional properties that identify type 2, namely, diffusion-controlled rates and absolute substrate specificity, whereas type 3b will be characterized by non-diffusion-controlled rates and absolute substrate specificity. We infer from this depiction of the three classes of enzymes, a general relation between the two functional properties, reaction rate and substrate specificity, namely, enzymes with diffusion-controlled rates have absolute substrate specificity. By appealing to energetic considerations, we furthermore show that enzymes with diffusion-controlled rates (types 2 and 3a) form a small subset of the class of all enzymes. This codification of present-day enzymes derived from an evolutionary model, essentially relates the structural properties of enzymes, as described by their thermodynamic parameters, to their functional properties, as represented by the reaction rate and substrate specificity.
本文依据一个模型对酶的反应速率和底物特异性的巨大多样性进行了整理和合理化阐释。该模型假定，当今酶的动力学特性是突变和选择的进化力量作用于一类催化活性差且底物特异性宽泛的原始酶的结果。根据酶在动力学上具有重要意义的过渡态中的热力学参数，即活化焓ΔH和活化熵ΔS，酶可分为以下几类：1型，ΔH*＞0，ΔS*＜0；2型，ΔH*≤0，ΔS*≤0；3型，ΔH*＞0，ΔS*＞0。我们研究了这三类酶在受到突变（作用于编码酶的基因水平）和选择（作用于含有该酶的生物体）时的进化动力学。我们的模型预测了这三类分子在反应速率和结合特异性方面的以下进化趋势。在1型酶中，进化导致反应速率和结合特异性发生随机、无方向性的变化。在2型和3型酶中，进化导致反应速率和结合特异性都单向增加。我们利用这些结果来整理当今酶功能特性的多样性。1型分子将以中等反应速率和宽泛的底物特异性来描述。2型酶的特征将是扩散控制的速率和绝对的底物特异性。3型催化剂可根据其活化焓进一步细分为两类：3a型（ΔH小）和3b型（ΔH大）。我们表明，3a型将具有与确定2型相同的功能特性，即扩散控制的速率和绝对的底物特异性，而3b型的特征将是非扩散控制的速率和绝对的底物特异性。从对这三类酶的描述中我们推断出反应速率和底物特异性这两个功能特性之间的一般关系，即具有扩散控制速率的酶具有绝对的底物特异性。通过考虑能量因素，我们还表明具有扩散控制速率的酶（2型和3a型）构成了所有酶类中的一个小子集。这种源自进化模型的当今酶的整理，本质上把酶的结构特性（由其热力学参数描述）与其功能特性（由反应速率和底物特异性表示）联系了起来。
