Human Lanosterol 14-Alpha Demethylase (CYP51A1) Is a Putative Target for Natural Flavonoid Luteolin 7,3'-Disulfate.
Leonid A KaluzhskiyPavel ErshovEvgeniy O YablokovTatsiana ShkelIrina GrabovecYuri MezentsevOksana GnedenkoSergey UsanovPolina ShabunyaSviatlana FatykhavaAlexander PopovAleksandr ArtyukovOlga StyshovaAndrei GilepNatallia StrushkevichAlexis IvanovPublished in: Molecules (Basel, Switzerland) (2021)
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.
Keyphrases
- molecular docking
- metabolic syndrome
- endothelial cells
- low density lipoprotein
- water soluble
- cardiovascular disease
- high throughput
- oxidative stress
- induced pluripotent stem cells
- type diabetes
- cell proliferation
- magnetic resonance imaging
- squamous cell carcinoma
- magnetic resonance
- poor prognosis
- adipose tissue
- risk assessment
- transcription factor
- cell wall
- dna methylation
- hepatitis c virus
- hiv infected
- high resolution
- antiretroviral therapy
- high speed
- genome wide