Abstract
A key metabolic adaptation of some species that face hypoxia as part of their life cycle involves an alternative electron transport chain in which rhodoquinone (RQ) is required for fumarate reduction and ATP production. RQ biosynthesis in bacteria and protists requires ubiquinone (Q) as a precursor. In contrast, Q is not a precursor for RQ biosynthesis in animals such as parasitic helminths, and most details of this pathway have remained elusive. Here, we used Caenorhabditis elegans as a model animal to elucidate key steps in RQ biosynthesis. Using RNAi and a series of C. elegans mutants, we found that arylamine metabolites from the kynurenine pathway are essential precursors for RQ biosynthesis de novo Deletion of kynu-1, encoding a kynureninase that converts l-kynurenine (KYN) to anthranilic acid (AA) and 3-hydroxykynurenine (3HKYN) to 3-hydroxyanthranilic acid (3HAA), completely abolished RQ biosynthesis but did not affect Q levels. Deletion of kmo-1, which encodes a kynurenine 3-monooxygenase that converts KYN to 3HKYN, drastically reduced RQ but not Q levels. Knockdown of the Q biosynthetic genes coq-5 and coq-6 affected both Q and RQ levels, indicating that both biosynthetic pathways share common enzymes. Our study reveals that two pathways for RQ biosynthesis have independently evolved. Unlike in bacteria, where amination is the last step in RQ biosynthesis, in worms the pathway begins with the arylamine precursor AA or 3HAA. Because RQ is absent in mammalian hosts of helminths, inhibition of RQ biosynthesis may have potential utility for targeting parasitic infections that cause important neglected tropical diseases.
Highlights
A key metabolic adaptation of some species that face hypoxia as part of their life cycle involves an alternative electron transport chain in which rhodoquinone (RQ) is required for fumarate reduction and ATP production
Unlike in bacteria, where amination is the last step in RQ biosynthesis, in worms the pathway begins with the arylamine precursor anthranilic acid (AA) or 3-hydroxyanthranilic acid (3HAA)
Because kynu-1 encodes a kynureninase that catalyzes the synthesis of two arylamines, anthranilic acid (AA) and 3-hydroxyanthranilic acid (3HAA), from L-kynurenine (KYN) and 3-hydroxy-L-kynurenine (3HKYN), respectively (Fig. 2A), we examined RQ biosynthesis in a kynu-1 KO strain
Summary
The kynurenine pathway is essential for rhodoquinone biosynthesis in Caenorhabditis elegans. 2 Present address: The Johns Hopkins University School of Medicine, 733 N. The biosynthetic pathway of RQ has been extensively studied in Rhodospirillum rubrum In this organism, RQ biosynthesis requires Q as a precursor [8]. The heterologous expression of R. rubrum rquA in two non-RQ–producing species, Escherichia coli and Saccharomyces cerevisiae, resulted in the in vivo conversion of native Q to synthetic RQ [12] Despite these advances, the biosynthesis of RQ in animals has not been elucidated, and the key genes involved have remained elusive. Because RQ is not synthesized or used by mammalian hosts, but is required for parasite survival, the RQ biosynthetic pathway is a unique target for antihelminthic drug design
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