Structural characterization of acyl-CoA oxidases reveals a direct link between pheromone biosynthesis and metabolic state in Caenorhabditis elegans
Structural characterization of acyl-CoA oxidases reveals a direct link between pheromone biosynthesis and metabolic state in Caenorhabditis elegans
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DOI：
10.1073/pnas.1608262113
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发表时间：
2016-09-06
影响因子：
11.1
通讯作者：
Butcher, Rebecca A.
中科院分区：
文献类型：
--
作者：
Zhang, Xinxing;Li, Kunhua;Butcher, Rebecca A.
秀丽线虫分泌蛔虫苷作为信息素，与其他蠕虫交流，协调种群的发育和行为。过氧化物体的β-氧化循环缩短了蛔虫苷前体的侧链，产生了短链的蛔虫苷信息素。在这些β-氧化循环中催化第一步的酰基辅酶A氧化酶具有不同的侧链长度特异性，使线虫能够调节特定的蛔虫苷信息素的产生。在这里，我们确定了酰基辅酶A氧化酶1(Acox-1)同源二聚体和与其底物结合的Acox-2同源二聚体的晶体结构。我们的结果为酰基辅酶A氧化酶的底物特异性提供了分子基础，并揭示了为什么其中一些酶具有非常广泛的底物范围，而另一些酶则非常特异。我们的结果也使我们能够预测在线虫和其他线虫物种中未知的酰基辅酶A氧化酶的作用。值得注意的是，我们发现大多数参与蛔虫苷生物合成的线虫酰基-CoA氧化酶都包含一个保守的ATP结合口袋，该口袋位于二聚体界面，我们确定了这个结合口袋中的关键残基。ATP结合诱导与FAD辅因子更紧密结合相关的结构变化。破坏ATP结合的突变会减少FAD结合并降低酶活性。因此，三磷酸腺苷可能作为酰基辅酶A氧化酶活性的调节剂，从而直接将蛔虫苷的生物合成与三磷酸腺苷的浓度和代谢状态联系起来。
Caenorhabditis elegans secretes ascarosides as pheromones to communicate with other worms and to coordinate the development and behavior of the population. Peroxisomal beta-oxidation cycles shorten the side chains of ascaroside precursors to produce the short-chain ascaroside pheromones. Acyl-CoA oxidases, which catalyze the first step in these beta-oxidation cycles, have different side chain-length specificities and enable C. elegans to regulate the production of specific ascaroside pheromones. Here, we determine the crystal structure of the acyl-CoA oxidase 1 (ACOX-1) homodimer and the ACOX-2 homodimer bound to its substrate. Our results provide a molecular basis for the substrate specificities of the acyl-CoA oxidases and reveal why some of these enzymes have a very broad substrate range, whereas others are quite specific. Our results also enable predictions to be made for the roles of uncharacterized acyl-CoA oxidases in C. elegans and in other nematode species. Remarkably, we show that most of the C. elegans acyl-CoA oxidases that participate in ascaroside biosynthesis contain a conserved ATP-binding pocket that lies at the dimer interface, and we identify key residues in this binding pocket. ATP binding induces a structural change that is associated with tighter binding of the FAD cofactor. Mutations that disrupt ATP binding reduce FAD binding and reduce enzyme activity. Thus, ATP may serve as a regulator of acyl-CoA oxidase activity, thereby directly linking ascaroside biosynthesis to ATP concentration and metabolic state.