Lanosterol

About: Lanosterol is a research topic. Over the lifetime, 1239 publications have been published within this topic receiving 36737 citations. The topic is also known as: (3β)-lanosta-8,24-dien-3-ol & (3β,20R)-lanosta-8,24-dien-3-ol.

Sterol Biosynthesis in Euglena gracilis Z.

Abstract: Squalene, squalene-2,3-oxide, triterpenes and 4α-methylsterols of Euglena gracilis Z. have been characterised by thin-layer chromatography, gas chromatography and mass spectrometry. Their distribution in dark-grown and light-grown Euglena cells is quantitatively and qualitatively different, reflecting differences in the sterol compositions. However the sterol precursor is found to be in each case cycloartenol, whereas lanosterol is not detected. A new 4α-methylsterol is isolated and the structure of 4α-24-dimethyl-5α-cholesta-8(9)-en-3s-ol proposed. 24-Methylene lanostenol is formed in light-grown Euglena. None of the compounds described have been found in water-soluble fractions nor in the form of fatty-acid esters. The following compounds have also been isolated: 24-methylene cycloartanol, 24-methylene agnostenol (?), s-amyrin, obtusifoliol, 24-methylene lophenol and 4α-methylzymosterol.

The conversion of [14C]cycloartenol and [14C)lanosterol into phytosterols by cultures of Nicotiana tabacum.

Abstract: Tissue cultures of Nicotiana tabacum were treated with [14C]cyeloartenol and [14C]lanosterol, and the 4,4-dimethylsterol 4-methylsterol and phytosterol fractions were examined for radioactivity. In both cases activity was incorporated into the phytosterols. The distributions of radioactivity in the 4,4-dimethylsterols and 4-methylsterols were compared with those obtained by incorporation of [14C]acetic acid. It is concluded that cycloartenol is a true phytosterol precursor in the tissue cultures, whereas the possible role of lanosterol (not detectable in the cultures, even by isotopic dilution experiments) is not proven.

Synthesis, Molecular Docking Studies, and Antifungal Activity Evaluation of New Benzimidazole-Triazoles as Potential Lanosterol 14α-Demethylase Inhibitors

Abstract: Due to anticandidal importance of azole compounds, a new series of benzimidazole-triazole derivatives (5a–5s) were designed and synthesized as ergosterol inhibitors. The chemical structures of the target compounds were characterized by spectroscopic methods. The final compounds were screened for antifungal activity against Candida glabrata (ATCC 90030), Candida krusei (ATCC 6258), Candida parapsilosis (ATCC 22019), and Candida albicans (ATCC 24433). Compounds 5i and 5s exhibited significant inhibitory activity against Candida strains with MIC50 values ranging from 0.78 to 1.56 μg/mL. Cytotoxicity results revealed that IC50 values of compounds 5i and 5s against NIH/3T3 are significantly higher than their MIC50 values. Effect of the compounds 5i and 5s against ergosterol biosynthesis was determined by LC-MS-MS analysis. Both compounds caused a significant decrease in the ergosterol level. The molecular docking studies were performed to investigate the interaction modes between the compounds and active site of lanosterol 14-α-demethylase (CYP51), which is as a target enzyme for anticandidal azoles. Theoretical ADME predictions were also calculated for final compounds.

Site-saturated mutagenesis of histidine 234 of Saccharomyces cerevisiae oxidosqualene-lanosterol cyclase demonstrates dual functions in cyclization and rearrangement reactions.

Abstract: Site-saturated mutagenesis experiments were carried out on the His234 residue of Saccharomyces cerevisiae oxidosqualene-lanosterol cyclase (ERG7) to characterize its functional role in ERG7 activity and to determine its effect on the oxidosqualene cyclization/rearrangement reaction. Two novel intermediates, (13alphaH)-isomalabarica-14(26),17E,21-trien-3beta-ol and protosta-20,24-dien-3beta-ol, isolated from ERG7(H234X) mutants, provided direct mechanistic evidence for formation of the chair-boat 6-6-5 tricyclic Markovnikov cation and protosteryl cation that were assigned provisionally to the ERG7-catalyzed biosynthetic pathway. In addition, we obtained mutants that showed a complete change in product specificity from lanosterol formation to either protosta-12,24-dien-3beta-ol or parkeol production. Finally, the repeated observation of multiple abortive and/or alternative cyclization/arrangement products from various ERG7(H234X) mutants demonstrated the catalytic plasticity of the enzyme. Specifically, subtle changes in the active site affect both the stability of the cation-pi interaction and generate product diversity.

Cytochrome P450 17α Hydroxylase/17,20 Lyase (CYP17) Function in Cholesterol Biosynthesis: Identification of Squalene Monooxygenase (Epoxidase) Activity Associated with CYP17 in Leydig Cells

Abstract: Cytochrome P450 17alpha-hydroxylase/17,20-lyase (CYP17) is a microsomal enzyme catalyzing two distinct activities, 17alpha-hydroxylase and 17,20-lyase, essential for the biosynthesis of adrenal and gonadal steroids. CYP17 is a potent oxidant, it is present in liver and nonsteroidogenic tissues, and it has been suggested to have catalytic properties distinct to its function in steroid metabolism. To identify CYP17 functions distinct of its 17alpha-hydroxylase/17,20-lyase activity, we used MA-10 mouse tumor Leydig cells known to be defective in 17alpha-hydroxylase/17,20-lyase activity. A CYP17 knocked down MA-10 clone (MA-10(CYP17KD)) was generated by homologous recombination and its steroidogenic capacity was compared with wild-type cells (MA-10(wt)). Although no differences in cell morphology and proliferation rates were observed between these cells, the human chorionic gonadotropin-induced progesterone formation and de novo synthesis of steroids were dramatically reduced in MA-10(CYP17KD) cells; their steroidogenic ability could be rescued in part by transfecting CYP17 DNA into the cells. Knocking down CYP17 mRNA by RNA interference yielded similar results. However, no significant difference was observed in the steroidogenic ability of cells treated with 22R-hydroxycholesterol, which suggested a defect in cholesterol biosynthesis. Incubation of MA-10(CYP17KD) cells with (14)C-labeled squalene resulted in the formation of reduced amounts of radiolabeled cholesterol compared with MA-10(wt) cells. In addition, treatment of MA-10(CYP17KD) cells with various cholesterol substrates indicated that unlike squalene, addition of squalene epoxide, lanosterol, zymosterol, and desmosterol could rescue the hormone-induced progesterone formation. Further in vitro studies demonstrated that expression of mouse CYP17 in bacteria resulted in the expression of squalene monooxygenase activity. In conclusion, these studies suggest that CYP17, in addition to its 17alpha-hydroxylase/17,20-lyase activity, critical in androgen formation, also expresses a secondary activity, squalene monooxygenase (epoxidase), of a well-established enzyme involved in cholesterol biosynthesis, which may become critical under certain conditions.