Clostridium scindens: a human gut microbe with a high potential to convert glucocorticoids into androgens |
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Authors: | Jason M Ridlon Shigeo Ikegawa Jo?o M P Alves Biao Zhou Akiko Kobayashi Takashi Iida Kuniko Mitamura Genzoh Tanabe Myrna Serrano Ainee De Guzman Patsy Cooper Gregory A Buck Phillip B Hylemon |
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Institution: | 2. Veterans Affairs McGuire Medical Center, Richmond, VA 23249;4. Faculty of Pharmaceutical Sciences, Kinki University, Kowakae, Higashi-Osaka 577-8502, Japan;11. Department of Chemistry, College of Humanities & Sciences, Nihon University, Sakurajousui, Setagaya, Tokyo 102-0074, Japan; and;8. Department of Biology, University of Virginia, Charlottesville, VA 22903 |
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Abstract: | Clostridium scindens American Type Culture Collection 35704 is capable of converting primary bile acids to toxic secondary bile acids, as well as converting glucocorticoids to androgens by side-chain cleavage. The molecular structure of the side-chain cleavage product of cortisol produced by C. scindens was determined to be 11β-hydroxyandrost-4-ene-3,17-dione (11β-OHA) by high-resolution mass spectrometry, 1H and 13C NMR spectroscopy, and X-ray crystallography. Using RNA-Seq technology, we identified a cortisol-inducible (∼1,000-fold) operon (desABCD) encoding at least one enzyme involved in anaerobic side-chain cleavage. The desC gene was cloned, overexpressed, purified, and found to encode a 20α-hydroxysteroid dehydrogenase (HSDH). This operon also encodes a putative “transketolase” (desAB) hypothesized to have steroid-17,20-desmolase/oxidase activity, and a possible corticosteroid transporter (desD). RNA-Seq data suggests that the two-carbon side chain of glucocorticords may feed into the pentose-phosphate pathway and are used as a carbon source. The 20α-HSDH is hypothesized to function as a metabolic “rheostat” controlling rates of side-chain cleavage. Phylogenetic analysis suggests this operon is rare in nature and the desC gene evolved from a gene encoding threonine dehydrogenase. The physiological effect of 11β-OHAD on the host or other gut microbes is currently unknown. |
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Keywords: | RNA-Seq microbiome steroid |
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