Barba Matthieu, Dutoit Raphaël, Legrain Christianne, Labedan Bernard
Institut de Génétique et Microbiologie, CNRS UMR 8621, Université Paris Sud, Bâtiment 400, 91405, Orsay Cedex, France.
BMC Syst Biol. 2013 Oct 5;7:99. doi: 10.1186/1752-0509-7-99.
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.
属于机制多样的超家族的酶通常表现出相似的催化机制。我们之前在环状酰胺水解酶超家族中观察到了这种关联，其成员在嘌呤和嘧啶代谢途径的相关步骤中发挥作用。为了建立酶同源性与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。
我们发现嘌呤和嘧啶途径的连续反应显示出相似的化学性质。这些机制相关的反应通常由同源酶催化。对相继的酶家族进行的一系列相似催化作用的检测表明，中心代谢的结构存在某种模块化。因此，我们引入反应模块的概念，以定义在可通过相似化学反应比对的途径中由同源酶催化的至少两个连续步骤。应用这一概念使我们能够为错误注释的旁系同源物提出新功能。特别是，我们发现了一种推定的脲基甘氨酸氨甲酰转移酶（UGTCase）活性。最后，我们提供了实验数据，支持该UGTCase可能参与嘌呤分解代谢新途径的结论。
使用反应模块概念应该具有很大价值。它将帮助我们追踪原始的混杂酶是如何随着当前途径从祖先途径分化出来以产生当今机制多样的超家族而逐渐组装成功能模块的。此外，该概念有助于确定错误注释蛋白质的实际功能。
