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Article

Human Lanosterol 14-Alpha Demethylase (CYP51A1) Is a Putative Target for Natural Flavonoid Luteolin 7,3′-Disulfate

by
Leonid Kaluzhskiy
1,*,
Pavel Ershov
1,
Evgeniy Yablokov
1,
Tatsiana Shkel
2,
Irina Grabovec
2,
Yuri Mezentsev
1,
Oksana Gnedenko
1,
Sergey Usanov
2,
Polina Shabunya
2,
Sviatlana Fatykhava
2,
Alexander Popov
3,
Aleksandr Artyukov
3,
Olga Styshova
3,
Andrei Gilep
2,
Natallia Strushkevich
4,* and
Alexis Ivanov
1
1
Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Street, 119121 Moscow, Russia
2
Institute of Bioorganic Chemistry NASB, 5 Building 2, V.F. Kuprevich Street, 220141 Minsk, Belarus
3
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Science, 159 Prospect 100-letiya Vladivostoka, 690022 Vladivostok, Russia
4
Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, bld. 1, 121205 Moscow, Russia
*
Authors to whom correspondence should be addressed.
Molecules 2021, 26(8), 2237; https://doi.org/10.3390/molecules26082237
Submission received: 10 March 2021 / Revised: 1 April 2021 / Accepted: 12 April 2021 / Published: 13 April 2021
(This article belongs to the Special Issue Dedicated to the 55th Anniversary of G.B. Elyakov Pacific Institute of Bioorganic Chemistry of the Far Eastern Branch of the Russian Academy of Sciences)
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Abstract

Widespread pathologies such as atherosclerosis, metabolic syndrome and cancer are associated with dysregulation of sterol biosynthesis and metabolism. Cholesterol modulates the signaling pathways of neoplastic transformation and tumor progression. Lanosterol 14-alpha demethylase (cytochrome P450(51), CYP51A1) catalyzes one of the key steps in cholesterol biosynthesis. The fairly low somatic mutation frequency of CYP51A1, its druggability, as well as the possibility of interfering with cholesterol metabolism in cancer cells collectively suggest the clinical importance of CYP51A1. Here, we show that the natural flavonoid, luteolin 7,3′-disulfate, inhibits CYP51A1 activity. We also screened baicalein and luteolin, known to have antitumor activities and low toxicity, for their ability to interact with CYP51A1. The Kd values were estimated using both a surface plasmon resonance optical biosensor and spectral titration assays. Unexpectedly, in the enzymatic activity assays, only the water-soluble form of luteolin—luteolin 7,3′-disulfate—showed the ability to potently inhibit CYP51A1. Based on molecular docking, luteolin 7,3′-disulfate binding suggests blocking of the substrate access channel. However, an alternative site on the proximal surface where the redox partner binds cannot be excluded. Overall, flavonoids have the potential to inhibit the activity of human CYP51A1 and should be further explored for their cholesterol-lowering and anti-cancer activity.
Keywords: lanosterol 14-alpha demethylase; flavonoids; enzyme inhibition; surface plasmon resonance; spectral titration; molecular docking lanosterol 14-alpha demethylase; flavonoids; enzyme inhibition; surface plasmon resonance; spectral titration; molecular docking

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MDPI and ACS Style

Kaluzhskiy, L.; Ershov, P.; Yablokov, E.; Shkel, T.; Grabovec, I.; Mezentsev, Y.; Gnedenko, O.; Usanov, S.; Shabunya, P.; Fatykhava, S.; et al. Human Lanosterol 14-Alpha Demethylase (CYP51A1) Is a Putative Target for Natural Flavonoid Luteolin 7,3′-Disulfate. Molecules 2021, 26, 2237. https://doi.org/10.3390/molecules26082237

AMA Style

Kaluzhskiy L, Ershov P, Yablokov E, Shkel T, Grabovec I, Mezentsev Y, Gnedenko O, Usanov S, Shabunya P, Fatykhava S, et al. Human Lanosterol 14-Alpha Demethylase (CYP51A1) Is a Putative Target for Natural Flavonoid Luteolin 7,3′-Disulfate. Molecules. 2021; 26(8):2237. https://doi.org/10.3390/molecules26082237

Chicago/Turabian Style

Kaluzhskiy, Leonid, Pavel Ershov, Evgeniy Yablokov, Tatsiana Shkel, Irina Grabovec, Yuri Mezentsev, Oksana Gnedenko, Sergey Usanov, Polina Shabunya, Sviatlana Fatykhava, and et al. 2021. "Human Lanosterol 14-Alpha Demethylase (CYP51A1) Is a Putative Target for Natural Flavonoid Luteolin 7,3′-Disulfate" Molecules 26, no. 8: 2237. https://doi.org/10.3390/molecules26082237

APA Style

Kaluzhskiy, L., Ershov, P., Yablokov, E., Shkel, T., Grabovec, I., Mezentsev, Y., Gnedenko, O., Usanov, S., Shabunya, P., Fatykhava, S., Popov, A., Artyukov, A., Styshova, O., Gilep, A., Strushkevich, N., & Ivanov, A. (2021). Human Lanosterol 14-Alpha Demethylase (CYP51A1) Is a Putative Target for Natural Flavonoid Luteolin 7,3′-Disulfate. Molecules, 26(8), 2237. https://doi.org/10.3390/molecules26082237

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