European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK.
Sci Signal. 2019 Aug 13;12(594):eaat9797. doi: 10.1126/scisignal.aat9797.
The 21st century is witnessing an explosive surge in our understanding of pseudoenzyme-driven regulatory mechanisms in biology. Pseudoenzymes are proteins that have sequence homology with enzyme families but that are proven or predicted to lack enzyme activity due to mutations in otherwise conserved catalytic amino acids. The best-studied pseudoenzymes are pseudokinases, although examples from other families are emerging at a rapid rate as experimental approaches catch up with an avalanche of freely available informatics data. Kingdom-wide analysis in prokaryotes, archaea and eukaryotes reveals that between 5 and 10% of proteins that make up enzyme families are pseudoenzymes, with notable expansions and contractions seemingly associated with specific signaling niches. Pseudoenzymes can allosterically activate canonical enzymes, act as scaffolds to control assembly of signaling complexes and their localization, serve as molecular switches, or regulate signaling networks through substrate or enzyme sequestration. Molecular analysis of pseudoenzymes is rapidly advancing knowledge of how they perform noncatalytic functions and is enabling the discovery of unexpected, and previously unappreciated, functions of their intensively studied enzyme counterparts. Notably, upon further examination, some pseudoenzymes have previously unknown enzymatic activities that could not have been predicted a priori. Pseudoenzymes can be targeted and manipulated by small molecules and therefore represent new therapeutic targets (or anti-targets, where intervention should be avoided) in various diseases. In this review, which brings together broad bioinformatics and cell signaling approaches in the field, we highlight a selection of findings relevant to a contemporary understanding of pseudoenzyme-based biology.
21 世纪见证了我们对生物学中伪酶驱动的调节机制的理解的爆炸式增长。伪酶是具有与酶家族序列同源性的蛋白质，但由于保守催化氨基酸的突变，已被证明或预测缺乏酶活性。研究最多的伪酶是假激酶，尽管随着实验方法赶上可用信息学数据的雪崩，其他家族的例子也在迅速出现。在原核生物、古菌和真核生物中进行的全基因组分析表明，组成酶家族的蛋白质中有 5%至 10%是伪酶，似乎与特定的信号位有关的明显扩张和收缩。伪酶可以变构激活典型酶，作为控制信号复合物组装及其定位的支架，作为分子开关，或通过底物或酶隔离来调节信号网络。对伪酶的分子分析正在迅速推进对它们如何执行非催化功能的认识，并使人们能够发现其经过深入研究的酶对应物的意想不到的和以前未被重视的功能。值得注意的是，经过进一步检查，一些伪酶以前具有未知的酶活性，这些活性是无法事先预测的。伪酶可以被小分子靶向和操纵，因此在各种疾病中代表新的治疗靶点（或反靶点，应该避免干预）。在这篇综述中，我们汇集了该领域广泛的生物信息学和细胞信号转导方法，强调了与基于伪酶的生物学的当代理解相关的一系列发现。
