Human Lanosterol 14-Alpha Demethylase (CYP51A1) Is a Putative Target for Natural Flavonoid Luteolin 7,3′-Disulfate
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
Affiliations
Leonid Kaluzhskiy
Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Street, 119121 Moscow, Russia
Pavel Ershov
Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Street, 119121 Moscow, Russia
Evgeniy Yablokov
Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Street, 119121 Moscow, Russia
Tatsiana Shkel
Institute of Bioorganic Chemistry NASB, 5 Building 2, V.F. Kuprevich Street, 220141 Minsk, Belarus
Irina Grabovec
Institute of Bioorganic Chemistry NASB, 5 Building 2, V.F. Kuprevich Street, 220141 Minsk, Belarus
Yuri Mezentsev
Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Street, 119121 Moscow, Russia
Oksana Gnedenko
Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Street, 119121 Moscow, Russia
Sergey Usanov
Institute of Bioorganic Chemistry NASB, 5 Building 2, V.F. Kuprevich Street, 220141 Minsk, Belarus
Polina Shabunya
Institute of Bioorganic Chemistry NASB, 5 Building 2, V.F. Kuprevich Street, 220141 Minsk, Belarus
Sviatlana Fatykhava
Institute of Bioorganic Chemistry NASB, 5 Building 2, V.F. Kuprevich Street, 220141 Minsk, Belarus
Alexander Popov
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
Aleksandr Artyukov
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
Olga Styshova
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
Andrei Gilep
Institute of Bioorganic Chemistry NASB, 5 Building 2, V.F. Kuprevich Street, 220141 Minsk, Belarus
Natallia Strushkevich
Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, bld. 1, 121205 Moscow, Russia
Alexis Ivanov
Institute of Biomedical Chemistry, 10 Building 8, Pogodinskaya Street, 119121 Moscow, Russia
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.
