Coenzyme Q (CoQ) is a lipidic compound that is widely distributed in nature, with crucial functions in metabolism, protection against oxidative damage and ferroptosis and other processes. CoQ biosynthesis is a conserved and complex pathway involving several proteins. COQ2 is a member of the UbiA family of transmembrane prenyltransferases that catalyzes the condensation of the head and tail precursors of CoQ, which is a key step in the process, because its product is the first intermediate that will be modified in the head by the next components of the synthesis process. Mutations in this protein have been linked to primary CoQ deficiency in humans, a rare disease predominantly affecting organs with a high energy demand. The reaction catalyzed by COQ2 and its mechanism are still unknown. Here, we aimed at clarifying the COQ2 reaction by exploring possible substrate binding sites using a strategy based on homology, comprising the identification of available ligand-bound homologs with solved structures in the Protein Data Bank (PDB) and their subsequent structural superposition in the AlphaFold predicted model for COQ2. The results highlight some residues located on the central cavity or the matrix loops that may be involved in substrate interaction, some of which are mutated in primary CoQ deficiency patients. Furthermore, we analyze the structural modifications introduced by the pathogenic mutations found in humans. These findings shed new light on the understanding of COQ2’s function and, thus, CoQ’s biosynthesis and the pathogenicity of primary CoQ deficiency.

中文翻译：

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作为辅酶 Q 合成复合物关键成分的 COQ2 的 AlphaFold 结构分析

辅酶Q（CoQ）是一种在自然界中广泛分布的脂质化合物，在新陈代谢、防止氧化损伤和铁死亡等过程中具有重要功能。 CoQ 生物合成是一条保守且复杂的途径，涉及多种蛋白质。 COQ2是跨膜异戊烯基转移酶UbiA家族的成员，它催化CoQ的头部和尾部前体的缩合，这是该过程中的关键步骤，因为它的产物是第一个中间体，将在头部被下一个修饰。合成过程的组成部分。这种蛋白质的突变与人类原发性 CoQ 缺乏症有关，这是一种主要影响能量需求高的器官的罕见疾病。 COQ2催化的反应及其机制尚不清楚。在这里，我们的目的是通过使用基于同源性的策略探索可能的底物结合位点来澄清 COQ2 反应，包括鉴定具有蛋白质数据库 (PDB) 中已解决结构的可用配体结合同源物以及它们随后在 AlphaFold 中的结构叠加COQ2 的预测模型。结果突出显示了位于中央腔或基质环上的一些残基，这些残基可能参与底物相互作用，其中一些残基在原发性 CoQ 缺乏症患者中发生突变。此外，我们分析了人类中发现的致病突变引起的结构修饰。这些发现为理解 COQ2 的功能以及 CoQ 的生物合成和原发性 CoQ 缺乏症的致病性提供了新的思路。