Metabolic Fate of Human Immunoactive Sterols in Mycobacterium tuberculosis

Varaksa, Tatsiana; Bukhdruker, Sergey; Grabovec, Irina; Marin, Egor; Kavaleuski, Anton; Gusach, Anastasiia; Kovalev, Kirill; Maslov, Ivan; Luginina, Aleksandra; Zabelskii, Dmitrii; Astashkin, Roman; Shevtsov, M.B.; Smolskaya, Sviatlana; Kavaleuskaya, Anna; Shabunya, Polina; Baranovsky, A. V.; Dolgopalets, V. I.; Charnou, Yury; Savachka, A. P.; Litvinovskaya, R. P.; Hurski, Alaksiej L.; Shevchenko, Evgeny; Rogachev, Andrey; Mishin, Alexey; Gordeliy, Valentin; Gabrielian, Andrei; Hurt, Darrell E.; Никоненко, Б. В.; Majorov, Konstantin; Апт, А. С.; Rosenthal, Alex; Gilep, Andrei A.; Borshchevskiy, Valentin; Strushkevich, Natallia

doi:10.1016/j.jmb.2020.166763

Cited by 17 publications

(22 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to the immunomodulatory effects, a recent study provided evidence that the enzymes produced by M. tuberculosis regulate the oxysterol metabolism to limit the effective induction of the immune response [ 63 ]. The mycobacterial enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD) can metabolize 25-OHC and 7α,25-OHC, among others, to render them inactive.…”

Section: Oxysterols In Bacterial Infectionsmentioning

confidence: 99%

“…The mycobacterial enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD) can metabolize 25-OHC and 7α,25-OHC, among others, to render them inactive. As these oxysterols have protective roles in immunity against M. tuberculosis , it is possible that 3β-HSD, along with the other identified Mtb enzymes CYP124, CYP125, and CYP142, targets these oxysterols to interfere with and evade the host immune response, thereby allowing its continual persistence in host macrophages [ 63 ]. It is also possible that M. tuberculosis produces itself antagonists against GPR183, as has been demonstrated for other bacteria.…”

Section: Oxysterols In Bacterial Infectionsmentioning

confidence: 99%

See 1 more Smart Citation

Oxysterols in the Immune Response to Bacterial and Viral Infections

Foo

Bartlett

Ronacher

2022

Cells

View full text Add to dashboard Cite

Oxidized cholesterols, the so-called oxysterols, are widely known to regulate cholesterol homeostasis. However, more recently oxysterols have emerged as important lipid mediators in the response to both bacterial and viral infections. This review summarizes our current knowledge of selected oxysterols and their receptors in the control of intracellular bacterial growth as well as viral entry into the host cell and viral replication. Lastly, we briefly discuss the potential of oxysterols and their receptors as drug targets for infectious and inflammatory diseases.

show abstract

Section: Oxysterols In Bacterial Infectionsmentioning

confidence: 99%

Section: Oxysterols In Bacterial Infectionsmentioning

confidence: 99%

Oxysterols in the Immune Response to Bacterial and Viral Infections

Foo

Bartlett

Ronacher

2022

Cells

View full text Add to dashboard Cite

show abstract

“…Analysis of high performance liquid chromatography (HPLC) profiles clearly demonstrate the formation of the product for all tested CYPs, indicating that recombinant RubB transferred electrons from the reductase to CYP. The amounts of products formed in the presence of RubB were comparable to that produced when the most efficient system with spinach ferredoxin was used [20]. Products were formed with significantly different efficiencies when reductases from various sources were used (Table 3), demonstrating the selectivity of RubB.…”

Section: Reconstitution Of Cyp Activitymentioning

confidence: 70%

A new twist of rubredoxin function inM. tuberculosis

Sushko

Kavaleuski

Grabovec

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Electron transfer mediated by metalloproteins drives many biological processes. Rubredoxins are ubiquitous iron-containing electron carriers that play important roles in bacterial adaptation to changing environmental conditions. In Mycobacterium tuberculosis, oxidative and acidic stresses as well as iron starvation induce rubredoxin expression. However, their functions during M. tuberculosis infection is unknown. In the present work, we show that rubredoxin B (RubB) supports catalytic activity of mycobacterial cytochrome P450s, CYP124, CYP125, and CYP142, which are important for bacterial viability and pathogenicity. We solved the crystal structure of RubB and characterized the interaction between RubB and CYPs using site-directed mutagenesis. Mutations that neutralized single charge on the surface of RubB did not dramatically decrease activity of studied CYPs, and isothermal calorimetry (ITC) experiments indicated that interactions are transient and not highly specific. Our findings suggest that a switch from ferredoxins to rubredoxins support CYP activity in M. tuberculosis-infected macrophages. Our electrochemical experiments suggest potential applications of RubB in biotechnology.

show abstract

“…What is the evidence in support of this idea? First, recombinant M. tuberculosis 3β-Hsd has been shown to convert cholesterol to cholestenone in vitro ( 29 , 35 ). M. tuberculosis lacking Rv1106c, the gene encoding 3β-Hsd, fail to convert cholesterol to cholestenone when growing in liquid culture, as shown by others ( 29 ) and verified by us ( Figure 4C ).…”

Section: Discussionmentioning

confidence: 99%

Macrophage global metabolomics identifies cholestenone as host/pathogen cometabolite present in human Mycobacterium tuberculosis infection

Chandra¹,

Coullon²,

Agarwal³

et al. 2022

Journal of Clinical Investigation

View full text Add to dashboard Cite

Mycobacterium tuberculosis ( M. tuberculosis ) causes an enormous burden of disease worldwide. As a central aspect of its pathogenesis, M. tuberculosis grows in macrophages, and host and microbe influence each other’s metabolism. To define the metabolic impact of M. tuberculosis infection, we performed global metabolic profiling of M. tuberculosis –infected macrophages. M. tuberculosis induced metabolic hallmarks of inflammatory macrophages and a prominent signature of cholesterol metabolism. We found that infected macrophages accumulate cholestenone, a mycobacterial-derived, oxidized derivative of cholesterol. We demonstrated that the accumulation of cholestenone in infected macrophages depended on the M. tuberculosis enzyme 3 β -hydroxysteroid dehydrogenase (3 β -Hsd) and correlated with pathogen burden. Because cholestenone is not a substantial human metabolite, we hypothesized it might be diagnostic of M. tuberculosis infection in clinical samples. Indeed, in 2 geographically distinct cohorts, sputum cholestenone levels distinguished subjects with tuberculosis (TB) from TB-negative controls who presented with TB-like symptoms. We also found country-specific detection of cholestenone in plasma samples from M. tuberculosis –infected subjects. While cholestenone was previously thought to be an intermediate required for cholesterol degradation by M. tuberculosis , we found that M. tuberculosis can utilize cholesterol for growth without making cholestenone. Thus, the accumulation of cholestenone in clinical samples suggests it has an alternative role in pathogenesis and could be a clinically useful biomarker of TB infection.

show abstract

Metabolic Fate of Human Immunoactive Sterols in Mycobacterium tuberculosis

Cited by 17 publications

References 70 publications

Oxysterols in the Immune Response to Bacterial and Viral Infections

Oxysterols in the Immune Response to Bacterial and Viral Infections

A new twist of rubredoxin function inM. tuberculosis

Macrophage global metabolomics identifies cholestenone as host/pathogen cometabolite present in human Mycobacterium tuberculosis infection

Contact Info

Product

Resources

About