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

Authors :
Leonid Kaluzhskiy
Pavel Ershov
Evgeniy Yablokov
Tatsiana Shkel
Irina Grabovec
Yuri Mezentsev
Oksana Gnedenko
Sergey Usanov
Polina Shabunya
Sviatlana Fatykhava
Alexander Popov
Aleksandr Artyukov
Olga Styshova
Andrei Gilep
Natallia Strushkevich
Alexis Ivanov
Source :
Molecules, Vol 26, Iss 8, p 2237 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

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.

Details

Language :
English
ISSN :
14203049
Volume :
26
Issue :
8
Database :
Directory of Open Access Journals
Journal :
Molecules
Publication Type :
Academic Journal
Accession number :
edsdoj.8f5b809dbd474750a69dc887199d5c98
Document Type :
article
Full Text :
https://doi.org/10.3390/molecules26082237