Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095-1569, United States.
J Phys Chem B. 2012 Sep 6;116(35):10649-56. doi: 10.1021/jp302771n. Epub 2012 Aug 27.
Ureases and metallo-β-lactamases are amide hydrolases closely related in function and structure. However, one major difference between them is that the former uses two nickel cations, and the latter uses two zinc cations to do similar catalytic jobs. What is the reason for this choice that Nature made for the catalytic metals? Is it dictated by electronic or structural reasons in the two catalyzed reactions, or some other evolutionary factors? Are both enzymes "perfect" catalysts, as far as just catalysis is concerned, and if they are, then why? Here, we address these questions through a joint quantum mechanical/molecular mechanical dynamics approach and ab initio mechanistic investigation. Five enzyme/substrate systems are considered: urease/urea, CcrA β-lactamase/β-lactam antibiotic model, urease/β-lactam antibiotic model, CcrA β-lactamase/urea, and di-Ni-substituted CcrA β-lactamase/β-lactam antibiotic model. The mechanisms and rates of the metal-facilitated nucleophilic attack are assessed. Both urease and Ni-substituted β-lactamase catalyze the attack on the β-lactam ring with the efficiency surpassing that of natural di-Zn β-lactamase, whereas β-lactamase is unable to hydrolyze urea. These results suggest that in β-lactamases the use of zinc does not provide maximal possible efficiency of the enzyme. Thus, β-lactamases operate by the principle of "good enough"; i.e., the choice for Zn in them leads to a performance that is just satisfactory for its biological purpose but can be evolutionarily improved via replacement of Zn with Ni.
脲酶和金属β-内酰胺酶在功能和结构上密切相关。然而，它们之间的一个主要区别是前者使用两个镍阳离子，而后者使用两个锌阳离子来完成类似的催化工作。大自然为什么会在催化金属方面做出这样的选择？这是由两个催化反应的电子或结构原因决定的，还是其他进化因素决定的？就催化作用而言，这两种酶都是“完美”的催化剂吗？如果是，那么为什么呢？在这里，我们通过联合量子力学/分子力学动力学方法和从头计算的机理研究来解决这些问题。考虑了五个酶/底物系统：脲酶/尿素、CcrA β-内酰胺酶/β-内酰胺抗生素模型、脲酶/β-内酰胺抗生素模型、CcrA β-内酰胺酶/尿素和双 Ni 取代的 CcrA β-内酰胺酶/β-内酰胺抗生素模型。评估了金属促进亲核攻击的机制和速率。脲酶和 Ni 取代的β-内酰胺酶都能有效地催化β-内酰胺环的亲核攻击，其效率超过天然双 Zn β-内酰胺酶，而β-内酰胺酶不能水解尿素。这些结果表明，在β-内酰胺酶中，锌的使用并不能提供酶的最大效率。因此，β-内酰胺酶的作用原理是“足够好”；也就是说，选择 Zn 导致的性能对于其生物目的来说只是令人满意的，但可以通过用 Ni 取代 Zn 来进化改进。
