Abstract:, 2016. Some chemical structures in the downstream AB-and CD-ring degradation pathways in Fig. 1 were incorrect. The revised Fig. 1 (below) shows the correct structures.
“…The final phase of estrogen degradation that encompasses the HIP degradation pathway follows a series of biochemical reactions involving enzymes similar to those for β-oxidation of fatty acids that in N. tardaugens are encoded in the SD cluster involved in the degradation of TES (Ibero et al, 2019a). Three pieces of evidence support that N. tardaugens uses the same gene products to degrade the C and D rings of both androgens and estrogens: (i) the SD cluster is upregulated in the presence of both E2 and TES compared with pyruvate; (ii) many of the genes contained in the SD cluster do not have other homologs in the N. tardaugens genome; and (iii) the predicted CD-ring degradation genes are highly conserved among different genera of steroidmetabolizing bacteria (Horinouchi et al, 2012(Horinouchi et al, , 2019Holert et al, 2016;Van Hamme et al, 2016;Crowe et al, 2017).…”
Section: Discussionmentioning
confidence: 93%
“…The degradation of A and B rings of steroids is achieved through different peripheral pathways depending on the compound, including the 9,10-seco pathway (for aerobic degradation of sterols and androgens), the 2,3-seco pathway (for the anaerobic degradation of sterols and androgens), and the 4,5seco pathway (for aerobic degradation of estrogens) (Wang et al, 2014;Van Hamme et al, 2016;Chen et al, 2017). The anaerobic degradation of estrogens has been described in the Denitratisoma sp.…”
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.
“…The final phase of estrogen degradation that encompasses the HIP degradation pathway follows a series of biochemical reactions involving enzymes similar to those for β-oxidation of fatty acids that in N. tardaugens are encoded in the SD cluster involved in the degradation of TES (Ibero et al, 2019a). Three pieces of evidence support that N. tardaugens uses the same gene products to degrade the C and D rings of both androgens and estrogens: (i) the SD cluster is upregulated in the presence of both E2 and TES compared with pyruvate; (ii) many of the genes contained in the SD cluster do not have other homologs in the N. tardaugens genome; and (iii) the predicted CD-ring degradation genes are highly conserved among different genera of steroidmetabolizing bacteria (Horinouchi et al, 2012(Horinouchi et al, , 2019Holert et al, 2016;Van Hamme et al, 2016;Crowe et al, 2017).…”
Section: Discussionmentioning
confidence: 93%
“…The degradation of A and B rings of steroids is achieved through different peripheral pathways depending on the compound, including the 9,10-seco pathway (for aerobic degradation of sterols and androgens), the 2,3-seco pathway (for the anaerobic degradation of sterols and androgens), and the 4,5seco pathway (for aerobic degradation of estrogens) (Wang et al, 2014;Van Hamme et al, 2016;Chen et al, 2017). The anaerobic degradation of estrogens has been described in the Denitratisoma sp.…”
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.
“…Homologs of ltp2 and chsH2 are found in sterol/bile acid degradation gene clusters of other bacteria, suggesting similar enzymes are used by diverse bacterial species to remove the last isopropyl side chains attached to the D-ring of various steroids (1,8,13). Here, we report the first structure of an Ltp2 in complex with the DUF35 domain of ChsH2.…”
mentioning
confidence: 85%
“…Certain bacteria from the actinobacteria and proteobacteria phyla have the unusual ability to utilize steroids as sole carbon sources (1,2). This microbial metabolic capacity is important for the removal of steroid waste in the environment, and the associated catabolic pathways have been exploited for the synthesis of steroidal pharmaceuticals (3).…”
“…The bacterial catabolism of sex steroids has been characterized at the molecular level [see 23 for a recent review]. Aerobic androgen catabolism through the steroid 9,10- seco pathway has been well characterized 24–26 ; it includes 3,17-dihydroxy-9,10- seco -androsta-1,3,5(10)-triene-9-one (3,17-DHSA) 27 and the 3-ketosteroid 9α-hydroxylase gene kshAB 28 as characteristic androgen metabolite and degradation genes, respectively. By using several denitrifying proteobacteria as the model organisms, we previously established an anaerobic degradation pathway (the steroid 2,3- seco pathway) for androgens; moreover, the 17β-hydroxy-1-oxo-2,3- seco -androstan-3-oic acid (abbreviated as 2,3-SAOA) 29 and atcABC encoding the 1-testosterone hydratase/dehydrogenase 30 were identified as the characteristic androgen metabolite and degradation genes for this anaerobic pathway, respectively.…”
Abnormally high circulating androgen levels have been considered a causative factor for benign prostatic hypertrophy and prostate cancer in men. Recent animal studies on gut microbiome suggested that gut bacteria are involved in sex steroid metabolism; however, the underlying mechanisms and bacterial taxa remain elusive. Denitrifying betaproteobacteria
Thauera
spp. are metabolically versatile and often distributed in the animal gut.
Thauera
sp. strain GDN1 is an unusual betaproteobacterium capable of catabolizing androgen under both aerobic and anaerobic conditions. We administered C57BL/6 mice (aged 7 weeks) with strain GDN1 through oral gavage. The strain GDN1 administration caused a minor increase in the relative abundance of
Thauera
(≤0.1%); however, it has profound effects on the host physiology and gut bacterial community. The results of our ELISA assay and metabolite profile analysis indicated an approximately 50% reduction in serum androgen levels in the strain GDN1-administered male mice. Moreover, androgenic ring-cleaved metabolites were detected in the fecal extracts of the strain GDN1-administered mice. Furthermore, our RT – qPCR results revealed the expression of the androgen catabolism genes in the gut of the strain GDN1-administered mice. We found that the administered strain GDN1 regulated mouse serum androgen levels, possibly because it blocked androgen recycling through enterohepatic circulation. This study discovered that sex steroids serve as a carbon source of gut bacteria; moreover, host circulating androgen levels may be regulated by androgen-catabolizing gut bacteria. Our data thus indicate the possible applicability of androgen-catabolic gut bacteria as potent probiotics in alternative therapy of hyperandrogenism.
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