The Actinobacterial mce4 Locus Encodes a Steroid Transporter

Mohn, William W.; Geize, Robert van der; Stewart, Gordon R.; Okamoto, Sachi; Liu, Jie; Dijkhuizen, Lubbert; Eltis, Lindsay D.

doi:10.1074/jbc.m805496200

Cited by 176 publications

(207 citation statements)

References 34 publications

Supporting

Mentioning

202

Contrasting

Order By: Relevance

“…The purification and characterization of the membrane transporters for the uptake of hydrophobic compounds is difficult, and the alternative strategy includes the identification of the transporter genes through mutagenesis. For example, by mutational analysis, Mohn et al (2008) identified the actinobacterial genes encoding the cholesterol transporter. Sdo.…”

Section: Discussionmentioning

confidence: 99%

Integrated multi-omics analyses reveal the biochemical mechanisms and phylogenetic relevance of anaerobic androgen biodegradation in the environment

et al. 2016

View full text Add to dashboard Cite

Steroid hormones, such as androgens, are common surface-water contaminants. However, literature on the ecophysiological relevance of steroid-degrading organisms in the environment, particularly in anoxic ecosystems, is extremely limited. We previously reported that Steroidobacter denitrificans anaerobically degrades androgens through the 2,3-seco pathway. In this study, the genome of Sdo. denitrificans was completely sequenced. Transcriptomic data revealed gene clusters that were distinctly expressed during anaerobic growth on testosterone. We isolated and characterized the bifunctional 1-testosterone hydratase/dehydrogenase, which is essential for anaerobic degradation of steroid A-ring. Because of apparent substrate preference of this molybdoenzyme, corresponding genes, along with the signature metabolites of the 2,3-seco pathway, were used as biomarkers to investigate androgen biodegradation in the largest sewage treatment plant in Taipei, Taiwan. Androgen metabolite analysis indicated that denitrifying bacteria in anoxic sewage use the 2,3-seco pathway to degrade androgens. Metagenomic analysis and PCR-based functional assays showed androgen degradation in anoxic sewage by Thauera spp. through the action of 1-testosterone hydratase/dehydrogenase. Our integrative 'omics' approach can be used for culture-independent investigations of the microbial degradation of structurally complex compounds where isotopelabeled substrates are not easily available.

show abstract

Section: Discussionmentioning

confidence: 99%

Integrated multi-omics analyses reveal the biochemical mechanisms and phylogenetic relevance of anaerobic androgen biodegradation in the environment

et al. 2016

View full text Add to dashboard Cite

show abstract

“…This strongly supports the idea that these 10 genes are specifically involved in sterol uptake. Ultimately, Mohn speculated that the proteins encoded by the mce4 loci might form a complex of ABC uptake transporters in the membrane of mycolate-containing bacteria to mediate the movement of the sterol substrates across the thick, hydrophobic cell envelope (Mohn, et al, 2008). This research on the biological function of the mce4 system provides us with new insight into the mechanism of active transport of phytosterols in the microbial transformation process.…”

Section: Affinity Uptake Of Sterolsmentioning

confidence: 99%

“…At the same time, they considered that there should be channels composed of sterol-binding or steroid-transforming proteins connecting the cytoplasm with the cell surface to reinforce the transport of sterols across the thick cell walls (Atrat, et al, 1991). In 2007 and 2008, van der Geize, Mohn, and their colleagues disclosed and substantiated the idea that there is a steroid uptake system in the gene cluster encoding sterol catabolism (van der Geize, et al, 2007;Mohn, et al, 2008). The steroid uptake system is a kind of mce4 ("mammalian cell entry") locus encoded by an operon including 10 genes conserved in diverse mycolate-containing actinobacteria.…”

Section: Affinity Uptake Of Sterolsmentioning

confidence: 99%

“…The steroid uptake system is a kind of mce4 ("mammalian cell entry") locus encoded by an operon including 10 genes conserved in diverse mycolate-containing actinobacteria. This locus is composed of two transmembrane permease (supAB) genes and eight mce4 protein (mce4ABCDEFHI) genes (Mohn, et al, 2008). The 10 genes have been shown to encode components of complex ATP-binding cassette ABC transporters.…”

Section: Affinity Uptake Of Sterolsmentioning

confidence: 99%

“…To increase their economic benefit, they should be reconstructed to avoid limitations in productivity. The phytosterol uptake capacity of the organisms should be enhanced by augmenting sterol transporters such as Mce proteins, and reducing the barrier effect of the cell envelope (Mohn, et al, 2008;Korycka-Machala, et al, 2005;Hoffmann, et al, 2008). The tolerance of the microbial cells to toxic products should be improved.…”

Section: The Future Of Phytosterol Productionmentioning

confidence: 99%

See 2 more Smart Citations

From Soybean Phytosterols to Steroid Hormones

Wang¹,

Yao²,

Wei³

2011

Soybean and Health

View full text Add to dashboard Cite

Structure Based Discovery of Inhibitors of CYP125 and CYP142 from Mycobacterium tuberculosis

Katariya

Snee

Tunnicliffe

et al. 2023

Chemistry A European J

View full text Add to dashboard Cite

Mycobacterium tuberculosis (Mtb) was responsible for approximately 1.6 million deaths in 2021. With the emergence of extensive drug resistance, novel therapeutic agents are urgently needed, and continued drug discovery efforts required. Host-derived lipids such as cholesterol not only support Mtb growth, but are also suspected to function in immunomodulation, with links to persistence and immune evasion. Mtb cytochrome P450 (CYP) enzymes facilitate key steps in lipid catabolism and thus present potential targets for inhibition. Here we present a series of compounds based on an ethyl 5-(pyridin-4-yl)-1H-indole-2-carboxylate pharmacophore which bind strongly to both Mtb cholesterol oxidases CYP125 and CYP142. Using a structure-guided approach, combined with biophysical characterization, compounds with micromolar range in-cell activity against clinically relevant drug-resistant isolates were obtained. These will incite further development of much-needed additional treatment options and provide routes to probe the role of CYP125 and CYP142 in Mtb pathogenesis.

show abstract

The Actinobacterial mce4 Locus Encodes a Steroid Transporter

Cited by 176 publications

References 34 publications

Integrated multi-omics analyses reveal the biochemical mechanisms and phylogenetic relevance of anaerobic androgen biodegradation in the environment

Integrated multi-omics analyses reveal the biochemical mechanisms and phylogenetic relevance of anaerobic androgen biodegradation in the environment

From Soybean Phytosterols to Steroid Hormones

Structure Based Discovery of Inhibitors of CYP125 and CYP142 from Mycobacterium tuberculosis

Contact Info

Product

Resources

About