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.

20Parasitic helminths infect over a billion humans. To survive in the low oxygen environment 21 of their hosts, these parasites use unusual anaerobic metabolism. This requires 22Rhodoquinone (RQ), an electron carrier that is made by very few animal species -23 crucially it is not present in any parasitic hosts. RQ synthesis is thus an ideal target for 24 anthelmintics but little is known about how RQ is made and no drugs are known to block 25 RQ synthesis. C.elegans makes RQ and can use RQ-dependent metabolic pathways -here, 26we use C.elegans genetics to identify the pathway for RQ synthesis and show that C.elegans 27 requires RQ for survival in hypoxic conditions. Finally, we establish a robust assay for 28 drugs that block RQ-dependent metabolism. This study identifies for the first time how RQ 29 is made in any animal and establishes a novel assay that can drive the development of a 30 new class of anthelmintic drugs. 31 32

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