title: The conserved Rieske oxygenase DAF-36/Neverland is a novel cholesterol-metabolizing enzyme.
abstract: Steroid hormones play essential roles in a wide variety of biological processes in multicellular organisms. The principal steroid hormones in nematodes and arthropods are dafachronic acids and ecdysteroids, respectively, both of which are synthesized from cholesterol as an indispensable precursor. The first critical catalytic step in the biosynthesis of these ecdysozoan steroids is the conversion of cholesterol to 7-dehydrocholesterol. However, the enzymes responsible for cholesterol 7,8-dehydrogenation remain unclear at the molecular level. Here we report that the Rieske oxygenase DAF-36/Neverland (Nvd) is a cholesterol 7,8-dehydrogenase. The daf-36/nvd genes are evolutionarily conserved, not only in nematodes and insects but also in deuterostome species that do not produce dafachronic acids or ecdysteroids, including the sea urchin Hemicentrotus pulcherrimus, the sea squirt Ciona intestinalis, the fish Danio rerio, and the frog Xenopus laevis. An in vitro enzymatic assay system reveals that all DAF-36/Nvd proteins cloned so far have the ability to convert cholesterol to 7-dehydrocholesterol. Moreover, the lethality of loss of nvd function in the fruit fly Drosophila melanogaster is rescued by the expression of daf-36/nvd genes from the nematode Caenorhabditis elegans, the insect Bombyx mori, or the vertebrates D. rerio and X. laevis. These data suggest that daf-36/nvd genes are functionally orthologous across the bilaterian phylogeny. We propose that the daf-36/nvd family of proteins is a novel conserved player in cholesterol metabolism across the animal phyla.
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Yoshiyama-Yanagawa
authors.forename: Sora
authors.initials: S
authors.lastname: Enya
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shimada-Niwa
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yaguchi
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Haramoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsuya
authors.forename: Kensuke
authors.initials: K
authors.lastname: Shiomi
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sasakura
authors.forename: Shuji
authors.initials: S
authors.lastname: Takahashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Asashima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kataoka
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Niwa
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000201:enzymology / Q000235:genetics; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D017124:Conserved Sequence; D003684:Dehydrocholesterols / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D019143:Evolution, Molecular; D008861:Microsomes / Q000378:metabolism; D008969:Molecular Sequence Data; D010105:Oxygenases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity
chemical_list: D003684:Dehydrocholesterols; D002784:Cholesterol; C016705:7-dehydrocholesterol; C510186:DAF-36 protein, C elegans; D010105:Oxygenases