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Lanosterol synthase

About: Lanosterol synthase is a research topic. Over the lifetime, 164 publications have been published within this topic receiving 5954 citations. The topic is also known as: lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase) & lanosterol synthase.


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Journal ArticleDOI
TL;DR: A robust chemical genomics approach is used to characterize expression profiles between D3T and CDDO-Im in livers from wild-type and Nrf2-null mice, providing novel insights into the pharmacodynamic action of these two activators of Keap1-Nrf2 signaling.
Abstract: The Kelch-like erythroid-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) signaling pathway is the subject of several clinical trials evaluating the effects of Nrf2 activation on the prevention of cancer and diabetes and the treatment of chronic kidney disease and multiple sclerosis. 3H-1,2-dithiole-3-thione (D3T) and 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are representative members of two distinct series of Nrf2 chemical activators. Previous reports have described activator-specific effects on Nrf2-dependent gene regulation and physiologic outcomes. Here we used a robust chemical genomics approach to characterize expression profiles between D3T and CDDO-Im in livers from wild-type and Nrf2-null mice. At equally efficacious doses in wild-type mice, 406 genes show common RNA responses to both treatments. These genes enriched the Nrf2-regulated pathways of antioxidant defense and xenobiotic metabolism. In addition, 197 and 745 genes were regulated uniquely in response to either D3T or CDDO-Im, respectively. Functional analysis of the D3T-regulated set showed a significant enrichment of Nrf2-regulated enzymes involved in cholesterol biosynthesis. This result was supported by Nrf2-dependent increases in lanosterol synthase and CYP51 protein expression. CDDO-Im had no effect on cholesterol biosynthesis regardless of the dose tested. However, unlike D3T, CDDO-Im resulted in Nrf2-dependent elevation of peroxisome proliferator α and Kruppel-like factor 13, as well as the coactivator peroxisome proliferator γ coactivator 1β, together indicating regulation of β-oxidation and lipid metabolic pathways. These findings provide novel insights into the pharmacodynamic action of these two activators of Keap1-Nrf2 signaling. Although both compounds modify Keap1 to affect canonical cytoprotective gene expression, additional unique sets of Nrf2-dependent genes were regulated by each agent with enrichment of selective metabolic pathways.

10 citations

Journal ArticleDOI
TL;DR: Crystal structure and homology modelling indicate that both enzymes possess a narrow constriction that separates an entrance lipophilic channel from the active-site cavity of squalene-hopene cyclase from Alicyclobacillus acidocaldarious and lanosterol synthase from Saccharomyces cerevisiae.
Abstract: Substrate access to the active-site cavity of squalene-hopene cyclase from Alicyclobacillus acidocaldarious and lanosterol synthase [OSC (oxidosqualene cyclase)] from Saccharomyces cerevisiae was studied by an inhibition, mutagenesis and homology-modelling approach. Crystal structure and homology modelling indicate that both enzymes possess a narrow constriction that separates an entrance lipophilic channel from the active-site cavity. The role of the constriction as a mobile gate that permits substrate passage was investigated by experiments in which critically located Cys residues, either present in native protein or inserted by site-directed mutagenesis, were labelled with specifically designed thiol-reacting molecules. Some amino acid residues of the yeast enzyme, selected on the basis of sequence alignment and a homology model, were individually replaced by residues bearing side chains of different lengths, charges or hydrophobicities. In some of these mutants, substitution severely reduced enzymatic activity and thermal stability. Homology modelling revealed that in these mutants some critical stabilizing interactions could no longer occur. The possible critical role of entrance channel and constriction in specific substrate recognition by eukaryotic OSC is discussed.

10 citations

Proceedings ArticleDOI
22 Apr 2020
TL;DR: The result indicated that quercetin, isoquercet in, and kaempferol from single bulb garlic could be potential ligand to treat hypercholesterolemia, and could proceed to in vitro and in vivo study by improving the absorption.
Abstract: Hypercholesterolemia is the highest risk of CVD which is the biggest disease leading death. One of the Indonesian medicinal plants is single bulb garlic with high flavonoids concentration. Lanosterol synthase, an enzyme on the final stage of cholesterol synthesis are the appropriate inhibition stage for drug. This study aimed to analyze the potential of single bulb garlic flavonoids (quercetin, isoquercetin, and kaempferol) in inhibiting lanosterol synthase. Computational docking analysis was performed using Pyrx, Pymol, Discovery studio, also webserver to predict ADMET and biological activity. Lanosterol synthase was obtained from PDB (PDB ID: IW6J) with RO 48-8071 as native ligand used for control. The results showed binding affinity RO 48-8071 (-10.3 kcal/mol), quercetin (-9.8 kcal/mol), isoquercetin (-6.8 kcal/mol), and kaempferol (-9.9 kcal/mol). Based on interaction and bonding distance, flavonoids have more stable than control. Flavonoids also have potential as APOA1, HMOX1 enhancers, lipid peroxidase inhibitors, cardioprotectant and hepatoprotectant, high distribution volumes, low toxicity, and clearance. This result indicated that quercetin, isoquercetin, and kaempferol from single bulb garlic could be potential ligand to treat hypercholesterolemia, and could proceed to in vitro and in vivo study by improving the absorption.

10 citations

Journal ArticleDOI
TL;DR: Novel analogues with a much lower pK(a) range gave potent oral inhibition of rat cholesterol biosynthesis, and diminished effects on rat feeding after a 100 mg/kg oral dose.

10 citations

Journal ArticleDOI
TL;DR: Extracts from 37 kinds of foods and foodstuffs were tested for inhibitory activity against recombinant human lanosterol synthase and eremanthine showed the most potent activity, 70% inhibition, at the concentration of 500 μM.
Abstract: Extracts from 37 kinds of foods and foodstuffs were tested for inhibitory activity against recombinant human lanosterol synthase. Among them, extracts from five samples showed significant inhibition. Potent activity (55%) was found in 95% ethanol extract of Laurus nobilis L. Therefore, large-scale methanol extraction of the plant was carried out, and the constituents were separated by partition and fractionation by silica gel chromatography and HPLC. Four flavonoids, kaemperol 3-O-[2″,4″-O-di-E-p-coumaroyl-α-l-pyranorhamnoside] (1); 3,3′,4′,5,6,7,8-heptamethoxyflavone (2); 3′,4′,5,6,7,8-hexamethoxyflavone (nobiletin) (3); and 4′,5,6,7,8-pentamethoxyflavone (tangeretin) (4); and six sesquiterpens, eremanthine (5), dehydrocostus lactone (6), costunolide (7), zaluzanin C (8), zaluzanin D (9) and reynosin (10) were isolated. Eremanthine (5) showed the most potent activity, 70% inhibition, at the concentration of 500 μM.

10 citations

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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
20216
20206
20194
20188
201711
20165