Abstract
We have analyzed the catabolism of estrogens in Novosphingobium tardaugens NBRC 16725, which is able to use endocrine disruptors such as 17β-estradiol, estrone, and estriol as sole carbon and energy sources. A transcriptomic analysis enabled the identification of a cluster of catabolic genes (edc cluster) organized in two divergent operons that are involved in estrogen degradation. We have developed genetic tools for this estrogen-degrading bacterium, allowing us to delete by site-directed mutagenesis some of the genes of the edc cluster and complement them by using expression plasmids to better characterize their precise role in the estrogen catabolism. Based on these results, a catabolic pathway is proposed. The first enzyme of the pathway (17β-hydroxysteroid dehydrogenase) used to transform 17β-estradiol into estrone is encoded out of the cluster. A CYP450 encoded by the edcA gene performs the second metabolic step, i.e., the 4-hydroxylation of estrone in this strain. The edcB gene encodes a 4-hydroxyestrone-4,5-dioxygenase that opens ring A after 4-hydroxylation. The initial steps of the catabolism of estrogens and cholate proceed through different pathways. However, the degradation of estrogens converges with the degradation of testosterone in the final steps of the lower catabolic pathway used to degrade the common intermediate 3aα-H-4α(3′-propanoate)7a-β-methylhexahydro-1,5-indanedione (HIP). The TonB-dependent receptor protein EdcT appears to be involved in estrogen uptake, being the first time that this kind of proteins has been involved in steroid transport.
Highlights
Estrogens are C18 steroid hormones synthetized in animals through the elimination of cholesterol side chain and play several physiological roles (Ryan, 1982)
There are some similarities with the previously described transcriptomic data for this strain when grown on TES compared to PYR (Ibero et al, 2019a): a slight differential induction of genes between EGO55_13695 and EGO55_13795 (SD cluster), induction of the methylmalonyl degradation pathway gene cluster, and high expression levels of genes involved in cobalamin synthesis pathway (Table S1)
In our previous work (Ibero et al, 2019a), we demonstrated that a 17β-hydroxysteroid dehydrogenase (17βHSD), encoded by EGO55_02230, transformed E2 to E1, and we reported similar expression levels in TES to those observed in E2-grown cells (Table S1), suggesting that its product could be responsible for the 17-dehydrogenation of both TES and E2
Summary
Estrogens are C18 steroid hormones synthetized in animals through the elimination of cholesterol side chain and play several physiological roles (Ryan, 1982). The occurrence and abundance of estrogens in aquatic environments present a serious risk to public health (Barbosa et al, 2016). They have been classified by the World Health Organization as group 1 carcinogens (https://monographs.iarc.fr/list-of-classifications-volumes/). Some biotransformation steps have been described in estrogen-degrading strains, the complete degradation pathway still remains unknown (Yu et al, 2013; Wang et al, 2014, 2018, 2019; Chen et al, 2017)
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