RRC ID 59580
Author Roberts Buceta PM, Romanelli-Cedrez L, Babcock SJ, Xun H, VonPaige ML, Higley TW, Schlatter TD, Davis DC, Drexelius JA, Culver JC, Carrera I, Shepherd JN, Salinas G.
Title The kynurenine pathway is essential for rhodoquinone biosynthesis in Caenorhabditis elegans.
Journal J Biol Chem
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.
Volume 294(28)
Pages 11047-11053
Published 2019-7-12
DOI 10.1074/jbc.AC119.009475
PII S0021-9258(20)30203-9
PMID 31177094
PMC PMC6635453
MeSH Animals Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / antagonists & inhibitors Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Chromatography, High Pressure Liquid Hydrolases / antagonists & inhibitors Hydrolases / genetics Hydrolases / metabolism Kynurenine / metabolism* Kynurenine 3-Monooxygenase / antagonists & inhibitors Kynurenine 3-Monooxygenase / genetics Kynurenine 3-Monooxygenase / metabolism Mass Spectrometry Methyltransferases / antagonists & inhibitors Methyltransferases / genetics Methyltransferases / metabolism Mitochondria / metabolism RNA Interference RNA, Double-Stranded / metabolism Subcutaneous Tissue / metabolism Ubiquinone / analogs & derivatives* Ubiquinone / analysis Ubiquinone / biosynthesis Ubiquinone / metabolism
IF 4.106
Times Cited 0
C.elegans tm4924 tm4529 tm4547 tm4627