TY  - JOUR
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
TI  - Metabolic Fate of Human Immunoactive Sterols in Mycobacterium tuberculosis
JO  - Journal of molecular biology
VL  - 433
IS  - 4
SN  - 0022-2836
CY  - Amsterdam [u.a.]
PB  - Elsevier
M1  - FZJ-2021-05889
SP  - 166763 -
PY  - 2021
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.
LB  - PUB:(DE-HGF)16
C6  - pmid:33359098
UR  - <Go to ISI:>//WOS:000616181400002
DO  - DOI:10.1016/j.jmb.2020.166763
UR  - https://juser.fz-juelich.de/record/904319
ER  -