Rhodoquinone biosynthesis in C. elegans requires precursors generated by the kynurenine pathway
Rhodoquinone biosynthesis in C. elegans requires precursors generated by the kynurenine pathway
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DOI：
10.7554/elife.48165
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发表时间：
2019-06-24
期刊：
影响因子：
7.7
通讯作者：
Fraser, Andrew G.
中科院分区：
文献类型：
--
作者：
Del Borrello, Samantha;Lautens, Margot;Fraser, Andrew G.
寄生蠕虫感染了超过十亿人。为了在宿主的低氧环境中生存，这些寄生虫使用不寻常的无氧代谢——这需要红醌（RQ），一种只有极少数动物才能产生的电子载体。至关重要的是，RQ不被任何寄生宿主制造或使用，因此RQ的合成是驱虫剂的理想目标。然而，人们对RQ是如何产生的知之甚少，也没有已知的药物可以阻断RQ的合成。秀丽隐杆线虫产生RQ，并可以使用RQ依赖的代谢途径-在这里，我们使用秀丽隐杆线虫遗传学来证明，色氨酸通过犬尿氨酸途径降解是生成RQ合成的关键含胺前体所必需的。我们发现秀丽隐杆线虫需要RQ才能在缺氧条件下存活，最后，我们建立了阻断RQ依赖代谢的药物的高通量测定。这可能会推动一类新型驱虫药的开发。这项研究是了解寄生蠕虫如何产生RQ的关键的第一步。
Parasitic helminths infect over a billion humans. To survive in the low oxygen environment of their hosts, these parasites use unusual anaerobic metabolism - this requires rhodoquinone (RQ), an electron carrier that is made by very few animal species. Crucially RQ is not made or used by any parasitic hosts and RQ synthesis is thus an ideal target for anthelmintics. However, little is known about how RQ is made and no drugs are known to block RQ synthesis. C. elegans makes RQ and can use RQ-dependent metabolic pathways - here, we use C. elegans genetics to show that tryptophan degradation via the kynurenine pathway is required to generate the key amine-containing precursors for RQ synthesis. We show that C. elegans requires RQ for survival in hypoxic conditions and, finally, we establish a high throughput assay for drugs that block RQ-dependent metabolism. This may drive the development of a new class of anthelmintic drugs. This study is a key first step in understanding how RQ is made in parasitic helminths.