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.Steroid hormones are crucial for development, growth, and homeostasis in multicellular organisms. Cholesterol and other sterol(s) serve as indispensable precursors for the biosynthesis of steroid hormones, and the conversion of cholesterol to the next specific intermediate is a crucial biochemical step across species (1-4). In the biosynthesis of vertebrate steroid hormones, cholesterol is commonly converted to pregnenolone by side-chain cleavage catalyzed by the cytochrome P450 monooxygenase P450scc/CYP11A1 (2). The step catalyzed by CYP11A1 is the key rate-limiting step in the synthesis of all vertebrate steroids, and it thus is controlled by numerous physiological responses throughout the life cycle (2, 5).Cholesterol is also required for steroid hormone biosynthesis in protostomes, including nematodes and arthropods (1, 6). However, the molecular mechanisms of cholesterol metabolism in these ecdysozoan animals have not been fully elucidated. The principal steroid hormones in nematodes and arthropods are dafachronic acids and ecdysteroids, respectively, both of which play pivotal roles in the regulation of developmental timing, reproduction, and longevity (1,7,8). In the biosynthesis of both dafachronic acids and ecdysteroids, which is different from the biosynthesis of vertebrate steroid hormones, cholesterol is converted to 7-dehydrocholesterol (7dC) 5 by dehydrogenation of the carbons at positions 7 and 8 (Fig. 1A) (9). Nematodes and arthropods lo...
Most living species exploit a limited range of resources. However, little is known on how tight links build up during evolution between specialist species and the hosts they utilize. We examined the dependence of Drosophila pachea on its single host, the senita cactus. Several amino acid changes in the Neverland oxygenase rendered D. pachea unable to transform cholesterol into 7-dehydrocholesterol (first reaction in the steroid hormone biosynthetic pathway in insects) and thus made D. pachea dependent on the uncommon sterols of its host plant. The neverland mutations increase survival on the cactus unusual sterols and are in a genomic region that faced recent positive selection. This study illustrates how relatively few genetic changes in a single gene may restrict the ecological niche of a species.
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