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@ARTICLE{Varaksa:904319,
author = {Varaksa, Tatsiana and Bukhdruker, Sergey and Grabovec,
Irina and Marin, Egor and Kavaleuski, Anton and Gusach,
Anastasiia and Kovalev, Kirill and Maslov, Ivan and
Luginina, Aleksandra and Zabelskii, Dmitrii and Astashkin,
Roman and Shevtsov, Mikhail and Smolskaya, Sviatlana and
Kavaleuskaya, Anna and Shabunya, Polina and Baranovsky,
Alexander and Dolgopalets, Vladimir and Charnou, Yury and
Savachka, Aleh and Litvinovskaya, Raisa and Hurski, Alaksiej
and Shevchenko, Evgeny and Rogachev, Andrey and Mishin,
Alexey and Gordeliy, Valentin and Gabrielian, Andrei and
Hurt, Darrell E. and Nikonenko, Boris and Majorov,
Konstantin and Apt, Alexander and Rosenthal, Alex and Gilep,
Andrei and Borshchevskiy, Valentin and Strushkevich,
Natallia},
title = {{M}etabolic {F}ate of {H}uman {I}mmunoactive {S}terols in
{M}ycobacterium tuberculosis},
journal = {Journal of molecular biology},
volume = {433},
number = {4},
issn = {0022-2836},
address = {Amsterdam [u.a.]},
publisher = {Elsevier},
reportid = {FZJ-2021-05889},
pages = {166763 -},
year = {2021},
abstract = {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.},
cin = {IBI-7},
ddc = {610},
cid = {I:(DE-Juel1)IBI-7-20200312},
pnm = {5241 - Molecular Information Processing in Cellular Systems
(POF4-524)},
pid = {G:(DE-HGF)POF4-5241},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:33359098},
UT = {WOS:000616181400002},
doi = {10.1016/j.jmb.2020.166763},
url = {https://juser.fz-juelich.de/record/904319},
}