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

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.

DHCR7 Expression Predicts Poor Outcomes and Mortality from Sepsis

“…CYP51A1 is critical for cholesterol synthesis, steroid synthesis, and drug metabolism. 41 LDLR encodes the LDL receptor which endocytoses LDL-C from circulation. 42 Both signi cant genes from the validation cohort were upregulated in CCI/early death patients compared to rapid recovery.…”

The Knowns and Unknowns in Protein–Metabolite Interactions

“…SPR requires small (in submicromolar range) amounts of analytes and allows measurement of kinetic parameters, as well as the dissociation constant (Kd). Consequently, this method is widely used to define the parameters of interaction between particular pairs of proteins and metabolites [ 74 , 75 , 76 ]. As an example, in a recent investigation dedicated to studying the interactions between an enzyme CYP51A1 and flavonoids, this enzyme was shown to be interacting with baicalein, luteolin and luteolin 7,3′-disulfate and the dissociation constants were defined in each case [ 76 ].…”

“…Consequently, this method is widely used to define the parameters of interaction between particular pairs of proteins and metabolites [ 74 , 75 , 76 ]. As an example, in a recent investigation dedicated to studying the interactions between an enzyme CYP51A1 and flavonoids, this enzyme was shown to be interacting with baicalein, luteolin and luteolin 7,3′-disulfate and the dissociation constants were defined in each case [ 76 ]. This method has a limitation in that metabolites with a smaller molecular mass induce only poorly detectable changes in the refractive index, but the sensitivity of the method can be improved significantly with gold nanoparticle chips [ 77 ].…”

The expression pattern, subcellular localization and function of three sterol 14α-demethylases in Aspergillus oryzae

“…Therefore, lacking this gene causes damage to membrane structure or function, which may eventually lead to the death of fungal, or affect plant growth and development process, or reducing animal the endogenous cholesterol synthesis, etc. Thus, CYP51 became important target for many antifungal drugs, herbicides and cholesterol-lowering drugs ( Lepesheva and Waterman, 2011 ; Zhang et al, 2019 ; Kaluzhskiy et al, 2021 ).…”