CAD is a 1.5 MDa particle formed by hexameric association of a 250 kDa protein divided into different enzymatic domains, each catalyzing one of the initial reactions for de novo biosynthesis of pyrimidine nucleotides: glutaminase-dependent Carbamoyl phosphate synthetase, Aspartate transcarbamoylase, and Dihydroorotase. The pathway for de novo pyrimidine synthesis is essential for cell proliferation and is conserved in all living organisms, but the covalent linkage of the first enzymatic activities into a multienzymatic CAD particle is unique to animals. In other organisms, these enzymatic activities are encoded as monofunctional proteins for which there is abundant structural and biochemical information. However, the knowledge about CAD is scarce and fragmented. Understanding CAD requires not only to determine the three-dimensional structures and define the catalytic and regulatory mechanisms of the different enzymatic domains, but also to comprehend how these domains entangle and work in a coordinated and regulated manner. This review summarizes significant progress over the past 10 years toward the characterization of CAD's architecture, function, regulatory mechanisms, and cellular compartmentalization, as well as the recent finding of a new and rare neurometabolic disorder caused by defects in CAD activities.

中文翻译：

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破译 CAD：一个超级酶嘧啶工厂在健康和疾病中的结构和功能

CAD 是一种 1.5 MDa 颗粒，由 250 kDa 蛋白质的六聚体结合形成，分为不同的酶促结构域，每个酶促结构域催化嘧啶核苷酸从头生物合成的初始反应之一：谷氨酰胺酶依赖性C氨基甲酰磷酸合成酶、A天冬氨酸转氨甲酰酶和D脱氢乳清酶。从头合成嘧啶的途径对于细胞增殖至关重要，并且在所有生物体中都是保守的，但第一个酶活性共价连接到多酶 CAD 颗粒中是动物所独有的。在其他生物体中，这些酶活性被编码为具有丰富结构和生化信息的单功能蛋白质。然而，关于 CAD 的知识是稀缺和零散的。理解CAD不仅需要确定三维结构并定义不同酶促结构域的催化和调节机制，还需要理解这些结构域如何以协调和调节的方式纠缠和工作。这篇综述总结了过去 10 年来在 CAD 架构表征方面的重大进展，