Enzymes belonging to mechanistically diverse superfamilies often display similar catalytic mechanisms. We previously observed such an association in the case of the cyclic amidohydrolase superfamily whose members play a role in related steps of purine and pyrimidine metabolic pathways. To establish a possible link between enzyme homology and chemical similarity, we investigated further the neighbouring steps in the respective pathways.
We identified that successive reactions of the purine and pyrimidine pathways display similar chemistry. These mechanistically-related reactions are often catalyzed by homologous enzymes. Detection of series of similar catalysis made by succeeding enzyme families suggested some modularity in the architecture of the central metabolism. Accordingly, we introduce the concept of a reaction module to define at least two successive steps catalyzed by homologous enzymes in pathways alignable by similar chemical reactions. Applying such a concept allowed us to propose new function for misannotated paralogues. In particular, we discovered a putative ureidoglycine carbamoyltransferase (UGTCase) activity. Finally, we present experimental data supporting the conclusion that this UGTCase is likely to be involved in a new route in purine catabolism.
Using the reaction module concept should be of great value. It will help us to trace how the primordial promiscuous enzymes were assembled progressively in functional modules, as the present pathways diverged from ancestral pathways to give birth to the present-day mechanistically diversified superfamilies. In addition, the concept allows the determination of the actual function of misannotated proteins.
机械多样的酶超家族中的酶通常显示出相似的催化机制。我们之前在环状酰胺水解酶超家族中观察到了这样的关联,其成员在嘌呤和嘧啶代谢途径的相关步骤中发挥作用。为了建立酶同源和化学相似性之间的可能联系,我们进一步研究了各自途径中的相邻步骤。
我们确定了嘌呤和嘧啶途径的连续反应显示出相似的化学反应。这些机制相关的反应通常由同源酶催化。检测到由连续酶家族进行的一系列相似催化反应,表明中心代谢的结构具有一定的模块化。因此,我们引入了反应模块的概念,以定义由类似化学反应可对齐的途径中由同源酶催化的至少两个连续步骤。应用这样的概念使我们能够为错注释的同源基因提出新的功能。特别是,我们发现了一种可能的尿素甘氨酸羧酰转移酶(UGTCase)活性。最后,我们提供实验数据支持结论,即这种UGTCase可能参与嘌呤降解中的新途径。
使用反应模块概念应该具有很大的价值。它将帮助我们追踪原始的杂合酶如何逐步组装成功能模块,随着现有途径从祖先途径分化出来,产生了现代机械多样的超家族。此外,该概念允许确定错注释蛋白质的实际功能。