TY - JOUR
T1 - Metabolic Fate of Human Immunoactive Sterols in Mycobacterium tuberculosis
AU - Varaksa, Tatsiana
AU - Bukhdruker, Sergey
AU - Grabovec, Irina
AU - Marin, Egor
AU - Kavaleuski, Anton
AU - Gusach, Anastasiia
AU - Kovalev, Kirill
AU - Maslov, Ivan
AU - Luginina, Aleksandra
AU - Zabelskii, Dmitrii
AU - Astashkin, Roman
AU - Shevtsov, Mikhail
AU - Smolskaya, Sviatlana
AU - Kavaleuskaya, Anna
AU - Shabunya, Polina
AU - Baranovsky, Alexander
AU - Dolgopalets, Vladimir
AU - Charnou, Yury
AU - Savachka, Aleh
AU - Litvinovskaya, Raisa
AU - Hurski, Alaksiej
AU - Shevchenko, Evgeny
AU - Rogachev, Andrey
AU - Mishin, Alexey
AU - Gordeliy, Valentin
AU - Gabrielian, Andrei
AU - Hurt, Darrell E.
AU - Nikonenko, Boris
AU - Majorov, Konstantin
AU - Apt, Alexander
AU - Rosenthal, Alex
AU - Gilep, Andrei
AU - Borshchevskiy, Valentin
AU - Strushkevich, Natallia
N1 - Funding Information:
We thank S. Fatykhava and O. Bokut for excellent technical assistance. We thank Prof. Rita Bernhardt (Saarland University, Saarbrucken, Germany) for providing the expression construct for Arh1. This work was supported by a joint research grant of the Belarusian Republican Foundation for Fundamental Research (X18P-098) and the Russian Foundation for Basic Research (18-54-00030). V.B. A.M. and A.R. are supported by the Ministry of Science and Higher Education of the Russian Federation (agreement # 075-00337-20-03, project FSMG-2020-0003). Mtb whole-cell assays in part were done under the theme of the Central Research Institute for Tuberculosis 0515-2014-0055 “Efficacy of TB drug therapy in dependence of the host genetics”. This work was supported in part by a grant from the NIAID (F.A. OISE-9531011 – Identification of Molecular Targets for Anti-Tuberculosis Drug Discovery). Any opinions, findings, and conclusions or recommendations expressed in this work are those of the author(s) and do not necessarily reflect the views of NIAID. We acknowledge the ESRF Structural Biology Group and especially A. N. Popov for assistance with crystallographic data collection. Thanks to the NIH Joint Center for Structural Genomics for the structure quality validation server. We appreciate a kind gift of G. Marchale (Institut Pasteur, Paris, France), who provided us with Mtb H37Rv (Pasteur). We are grateful to Richard Lozier for editing our manuscript. A.Gi. and E.S. are employees of MT-Medicals LLC. The other authors declare no competing interests.
Funding Information:
We thank S. Fatykhava and O. Bokut for excellent technical assistance. We thank Prof. Rita Bernhardt (Saarland University, Saarbrucken, Germany) for providing the expression construct for Arh1. This work was supported by a joint research grant of the Belarusian Republican Foundation for Fundamental Research (X18P-098) and the Russian Foundation for Basic Research (18-54-00030). V.B., A.M. and A.R. are supported by the Ministry of Science and Higher Education of the Russian Federation (agreement # 075-00337-20-03, project FSMG-2020-0003). Mtb whole-cell assays in part were done under the theme of the Central Research Institute for Tuberculosis 0515-2014-0055 “Efficacy of TB drug therapy in dependence of the host genetics”. This work was supported in part by a grant from the NIAID (F.A. OISE-9531011 – Identification of Molecular Targets for Anti-Tuberculosis Drug Discovery). Any opinions, findings, and conclusions or recommendations expressed in this work are those of the author(s) and do not necessarily reflect the views of NIAID. We acknowledge the ESRF Structural Biology Group and especially A. N. Popov for assistance with crystallographic data collection. Thanks to the NIH Joint Center for Structural Genomics for the structure quality validation server. We appreciate a kind gift of G. Marchale (Institut Pasteur, Paris, France), who provided us with Mtb H37Rv (Pasteur). We are grateful to Richard Lozier for editing our manuscript.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2021/2/19
Y1 - 2021/2/19
N2 - Mycobacterium tuberculosis (Mtb) infection is among top ten causes of death worldwide, and the number of drug-resistant strains is increasing. The direct interception of human immune signaling molecules by Mtb remains elusive, limiting drug discovery. Oxysterols and secosteroids regulate both innate and adaptive immune responses. Here we report a functional, structural, and bioinformatics study of Mtb enzymes initiating cholesterol catabolism and demonstrated their interrelation with human immunity. We show that these enzymes metabolize human immune oxysterol messengers. Rv2266 – the most potent among them – can also metabolize vitamin D3 (VD3) derivatives. High-resolution structures show common patterns of sterols binding and reveal a site for oxidative attack during catalysis. Finally, we designed a compound that binds and inhibits three studied proteins. The compound shows activity against Mtb H37Rv residing in macrophages. Our findings contribute to molecular understanding of suppression of immunity and suggest that Mtb has its own transformation system resembling the human phase I drug-metabolizing system.
AB - Mycobacterium tuberculosis (Mtb) infection is among top ten causes of death worldwide, and the number of drug-resistant strains is increasing. The direct interception of human immune signaling molecules by Mtb remains elusive, limiting drug discovery. Oxysterols and secosteroids regulate both innate and adaptive immune responses. Here we report a functional, structural, and bioinformatics study of Mtb enzymes initiating cholesterol catabolism and demonstrated their interrelation with human immunity. We show that these enzymes metabolize human immune oxysterol messengers. Rv2266 – the most potent among them – can also metabolize vitamin D3 (VD3) derivatives. High-resolution structures show common patterns of sterols binding and reveal a site for oxidative attack during catalysis. Finally, we designed a compound that binds and inhibits three studied proteins. The compound shows activity against Mtb H37Rv residing in macrophages. Our findings contribute to molecular understanding of suppression of immunity and suggest that Mtb has its own transformation system resembling the human phase I drug-metabolizing system.
KW - 25-hydroxy-cholesterol
KW - CYP crystal structure
KW - Mycobacterium tuberculosis
KW - host-pathogen interactions
KW - immunity
UR - http://www.scopus.com/inward/record.url?scp=85100155575&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2020.166763
DO - 10.1016/j.jmb.2020.166763
M3 - Article
C2 - 33359098
AN - SCOPUS:85100155575
VL - 433
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
SN - 0022-2836
IS - 4
M1 - 166763
ER -
