Metabolic Fate of Human Immunoactive Sterols in Mycobacterium tuberculosis.

3-Hydroxysteroid Dehydrogenases / chemistry Catalysis Cytochrome P-450 Enzyme System / chemistry Energy Metabolism Enzyme Activation Host-Pathogen Interactions / immunology Humans Immunity Isoenzymes Models, Molecular Mycobacterium tuberculosis / immunology Oxysterols / chemistry Recombinant Proteins Structure-Activity Relationship Tuberculosis / immunology
25-hydroxy-cholesterol CYP crystal structure Mycobacterium tuberculosis host-pathogen interactions immunity

Journal

Journal of molecular biology
ISSN: 1089-8638
Titre abrégé: J Mol Biol
Pays: Netherlands
ID NLM: 2985088R

Informations de publication

Date de publication:
19 02 2021
Historique:
received: 15 08 2020
revised: 05 12 2020
accepted: 12 12 2020
pubmed: 29 12 2020
medline: 24 4 2021
entrez: 28 12 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.jmb.2020.166763 PMID: 33359098
pubmed: 33359098
pii: S0022-2836(20)30688-4
doi: 10.1016/j.jmb.2020.166763
pii:
doi:

Substances chimiques

Isoenzymes 0
Oxysterols 0
Recombinant Proteins 0
Cytochrome P-450 Enzyme System 9035-51-2
3-Hydroxysteroid Dehydrogenases EC 1.1.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

166763

Informations de copyright

Copyright © 2020 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests A.Gi. and E.S. are employees of MT-Medicals LLC. The other authors declare no competing interests.

Auteurs

Tatsiana Varaksa (T)

Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus.

Sergey Bukhdruker (S)

Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, Russia; Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Research Center Jülich, Jülich, Germany; JuStruct: Jülich Center for Structural Biology, Research Center Jülich, Jülich, Germany; ESRF-The European Synchrotron, Grenoble, France.

Irina Grabovec (I)

Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus.

Egor Marin (E)

Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, Russia.

Anton Kavaleuski (A)

Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus.

Anastasiia Gusach (A)

Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, Russia.

Kirill Kovalev (K)

Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, Russia.

Ivan Maslov (I)

Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, Russia.

Aleksandra Luginina (A)

Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, Russia.

Dmitrii Zabelskii (D)

Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, Russia; Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Research Center Jülich, Jülich, Germany; JuStruct: Jülich Center for Structural Biology, Research Center Jülich, Jülich, Germany.

Roman Astashkin (R)

Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, Russia.

Mikhail Shevtsov (M)

Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, Russia.

Sviatlana Smolskaya (S)

Sechenov First Moscow State Medical University, Moscow, Russia.

Anna Kavaleuskaya (A)

Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus.

Polina Shabunya (P)

Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus.

Alexander Baranovsky (A)

Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus.

Vladimir Dolgopalets (V)

Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus.

Yury Charnou (Y)

Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus.

Aleh Savachka (A)

Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus.

Raisa Litvinovskaya (R)

Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus.

Alaksiej Hurski (A)

Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus.

Evgeny Shevchenko (E)

MT-Medicals LLC, Moscow, Russia.

Andrey Rogachev (A)

Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, Russia; Joint Institute for Nuclear Research, Dubna, Russia.

Alexey Mishin (A)

Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, Russia.

Valentin Gordeliy (V)

Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, Russia; Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Research Center Jülich, Jülich, Germany; JuStruct: Jülich Center for Structural Biology, Research Center Jülich, Jülich, Germany; Institute of Crystallography, University of Aachen (RWTH), Aachen, Germany.

Andrei Gabrielian (A)

Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.

Darrell E Hurt (DE)

Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.

Boris Nikonenko (B)

Central Institute for Tuberculosis, Moscow, Russia.

Konstantin Majorov (K)

Central Institute for Tuberculosis, Moscow, Russia.

Alexander Apt (A)

Central Institute for Tuberculosis, Moscow, Russia.

Alex Rosenthal (A)

Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.

Andrei Gilep (A)

Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus; Institute of Biomedical Chemistry, Moscow, Russia; MT-Medicals LLC, Moscow, Russia.

Valentin Borshchevskiy (V)

Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology (MIPT), Dolgoprudny, Russia; Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Research Center Jülich, Jülich, Germany; JuStruct: Jülich Center for Structural Biology, Research Center Jülich, Jülich, Germany. Electronic address: borshchevskiy.vi@phystech.edu.

Natallia Strushkevich (N)

Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus; Skolkovo Institute of Science and Technology, Moscow, Russia. Electronic address: N.Strushkevich@skoltech.ru.

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Classifications MeSH

questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Alcohol oxidoreductases › Hydroxysteroid dehydrogenases › 3-Hydroxysteroid dehydrogenases › Metabolic Fate of Human Immunoactive Sterols...
questionsmedicales.fr › Phénomènes chimiques › Catalyse › Metabolic Fate of Human Immunoactive Sterols...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Hémoprotéines › Cytochromes › Cytochrome P-450 enzyme system › Metabolic Fate of Human Immunoactive Sterols...
questionsmedicales.fr › Métabolisme › Métabolisme énergétique › Metabolic Fate of Human Immunoactive Sterols...
questionsmedicales.fr › Métabolisme › Activation enzymatique › Metabolic Fate of Human Immunoactive Sterols...
questionsmedicales.fr › Phénomènes biologiques › Interactions hôte-microbes › Interactions hôte-pathogène › Metabolic Fate of Human Immunoactive Sterols...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Metabolic Fate of Human Immunoactive Sterols...
questionsmedicales.fr › Phénomènes du système immunitaire › Immunité › Metabolic Fate of Human Immunoactive Sterols...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Isoformes de protéines › Isoenzymes › Metabolic Fate of Human Immunoactive Sterols...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles moléculaires › Metabolic Fate of Human Immunoactive Sterols...
questionsmedicales.fr › Bactéries › Bactéries à Gram positif › Bâtonnets à Gram positif › Bâtonnets asporogènes à Gram positif › Bâtonnets asporogènes réguliers à Gram positif › Mycobacteriaceae › Mycobacterium › Mycobacterium tuberculosis › Metabolic Fate of Human Immunoactive Sterols...
questionsmedicales.fr › Lipides › Lipides membranaires › Stérols › Cholestérol › Oxystérols › Metabolic Fate of Human Immunoactive Sterols...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines recombinantes › Metabolic Fate of Human Immunoactive Sterols...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Metabolic Fate of Human Immunoactive Sterols...
questionsmedicales.fr › Infection › Infections bactériennes et mycoses › Infections bactériennes › Infections bactériennes à Gram positif › Infections à Actinomycetales › Infections à Mycobacterium › Tuberculose › Metabolic Fate of Human Immunoactive Sterols...