Variations within class-A β-lactamase physiochemical properties reflect evolutionary and environmental patterns, but not antibiotic specificity.
Variations within class-A β-lactamase physiochemical properties reflect evolutionary and environmental patterns, but not antibiotic specificity.
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DOI：
10.1371/journal.pcbi.1003155
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发表时间：
2013
影响因子：
4.3
通讯作者：
Livesay DR
中科院分区：
文献类型：
--
作者：
Verma D;Jacobs DJ;Livesay DR
细菌酶β-内酰胺酶会水解青霉素和化学相关抗生素的β-内酰胺环，使它们失效。由于抗生素过度使用的猖獗，这种酶正在以惊人的速度进化出新的耐药活性。相关的是，该酶的整体理化特性在整个家族中表现出不同程度的保守性和变异性。为此，我们描述了 12 种不同的 A 类 β-内酰胺酶内的性质保守程度，并最终确定其中的系统变异与其进化历史平行。在整个蛋白质中观察到静电势图和成对残基到残基耦合的巨大且系统的差异，这有力地反映了系统发育外群。其他特性更加保守（例如残基 pKa 值、静电网络和主链柔性），但它们也具有以统计显着方式与系统发育平行的系统变化。类似地，上述特性也以统计上显着的方式与它们所来自的细菌的环境条件相似。然而，有趣且令人惊讶的是，唯一的全局特性（蛋白质电荷）与功能特异性模式相似；这意味着抗生素耐药性活动并没有显着限制整体的理化特性。相反，扩展频谱活动可以从几乎任何一组静电和动态特性的背景中出现。蛋白质序列和结构共享功能的比较已成为一种成熟的生物信息学范式，导致与蛋白质家族序列/结构/功能关系相关的无数发现。然而，序列和结构本身仅提供粗略的理化描述，因此强调需要更复杂的分析。在这项工作中，我们确定了 β-内酰胺酶家族的动力学和静电特性有多大差异。我们的结果表明，一些特性在整个家族中大多是保守的，而其他特性则存在显着差异，尽管它们都具有相同的高水平 β-内酰胺酶活性。尽管某些指标存在全局差异，但在进化外群体之间经常观察到系统差异，这表明理化特性既保守又可变。因此，这些结果强调了整个蛋白质家族理化特性的丰富性，并提供了对变异如何产生的见解。
The bacterial enzyme β-lactamase hydrolyzes the β-lactam ring of penicillin and chemically related antibiotics, rendering them ineffective. Due to rampant antibiotic overuse, the enzyme is evolving new resistance activities at an alarming rate. Related, the enzyme's global physiochemical properties exhibit various amounts of conservation and variability across the family. To that end, we characterize the extent of property conservation within twelve different class-A β-lactamases, and conclusively establish that the systematic variations therein parallel their evolutionary history. Large and systematic differences within electrostatic potential maps and pairwise residue-to-residue couplings are observed across the protein, which robustly reflect phylogenetic outgroups. Other properties are more conserved (such as residue pKa values, electrostatic networks, and backbone flexibility), yet they also have systematic variations that parallel the phylogeny in a statistically significant way. Similarly, the above properties also parallel the environmental condition of the bacteria they are from in a statistically significant way. However, it is interesting and surprising that the only one of the global properties (protein charge) parallels the functional specificity patterns; meaning antibiotic resistance activities are not significantly constraining the global physiochemical properties. Rather, extended spectrum activities can emerge from the background of nearly any set of electrostatic and dynamic properties. Comparison of protein sequences and structures sharing function has become a well-established bioinformatics paradigm, leading to countless discoveries related to protein family sequence/structure/function relationships. However, sequence and structure alone provide only crude physiochemical descriptions, thus stressing the need for more sophisticated analyses. In this work, we determine how much dynamical and electrostatic properties vary across the β-lactamase enzyme family. Our results indicate that some properties are mostly conserved across the family, whereas others vary significantly despite the fact that all share the same high-level β-lactamase activity. Despite global variance in some metrics, systematic differences are frequently observed between evolutionary outgroups, indicating that physiochemical properties are simultaneously conserved and variable. As such, these results underscore the richness within physiochemical properties across a protein family and provide insight into how the variations came about.
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