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Edited by Catherine L. Drennan, Massachusetts Institute of Technology, Cambridge, MA, and accepted by Editorial Board Member Caroline S. Harwood November 20, 2019 (received for review August 26, 2019)
Significance
Steroids are mainly produced by animals, while bacteria are major steroid consumers in the biosphere. Anaerobic environments are major reservoirs for estrogens; however, prior to this study, biochemical mechanisms involved in anaerobic estrogen catabolism remained completely unknown. Here, we characterized anaerobic estrogen catabolic pathway in denitrifying Denitratisoma sp. strain DHT3, which includes the transformation of estrogens into androgens via a cobalamin-dependent methylation. Data presented here complete the central pathways for bacterial steroid catabolism and reveal an unprecedented role of cobalamin in microbial steroid metabolism. Sex steroids are involved in bidirectional metabolic interactions between bacteria and their eukaryotic hosts; the discovery of retroconversion of estrogens into androgens in bacteria portends unexplored microbe–host metabolic interdependencies via this cobalamin-dependent estrogen methylation reaction.
Abstract
Steroid estrogens modulate physiology and development of vertebrates. Conversion of C19 androgens into C18 estrogens is thought to be an irreversible reaction. Here, we report a denitrifying Denitratisoma sp. strain DHT3 capable of catabolizing estrogens or androgens anaerobically. Strain DHT3 genome contains a polycistronic gene cluster, emtABCD, differentially transcribed under estrogen-fed conditions and predicted to encode a cobalamin-dependent methyltransferase system conserved among estrogen-utilizing anaerobes; an emtA-disrupted DHT3 derivative could catabolize androgens but not estrogens. These data, along with the observed androgen production in estrogen-fed strain DHT3 cultures, suggested the occurrence of a cobalamin-dependent estrogen methylation to form androgens. Consistently, the estrogen conversion into androgens in strain DHT3 cell extracts requires methylcobalamin and is inhibited by propyl iodide, a specific inhibitor of cobalamin-dependent enzymes. The identification of the cobalamin-dependent estrogen methylation thus represents an unprecedented metabolic link between cobalamin and steroid metabolism and suggests that retroconversion of estrogens into androgens occurs in the biosphere.
Footnotes
↵1Present address: Earth-Life Science Institute, Tokyo Institute of Technology, 152-8550 Tokyo, Japan.
↵2Present address: State Key Laboratory of Marine Environmental Science, College of Ocean and Earth Sciences, Xiamen University, 361102 Xiamen, China.
- ↵3To whom correspondence may be addressed. Email: yinru915{at}gate.sinica.edu.tw.
Author contributions: P.-H.W., Y.-L.C., and Y.-R.C. designed research; S.T.-S.W., K.W., and T.-Y.W. performed research; T.-H.L. contributed new reagents/analytic tools; P.-H.W., Y.-L.C., and Y.-R.C. analyzed data; and P.-H.W. and Y.-R.C. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission. C.L.D. is a guest editor invited by the Editorial Board.
Data deposition: The genome sequence of the strain DHT3 has been deposited in the National Center for Biotechnology Information (NCBI) Genome database (accession no. CP020914). The transcriptomes of the strain DHT3 have been deposited in the NCBI database (accession nos. SRR10362955 and SRR10362956).
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This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1914380117/-/DCSupplemental.
Published under the PNAS license.
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Retroconversion of estrogens into androgens by bacteria via a cobalamin-mediated methylation
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