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 via lanosterol by the trypanosomid Crithidia fasciculata

Abstract: Incorporation of [1-14 C]acetate by the trypanosomid Crithidia fasciculata showed that ergosterol biosynthesis occurs de novo in this protozoon, via lanosterol and 31-norlanosterol. No cycloartenol could be detected, indicating that this biosynthesis pathway is rather similar to those of other non-photosynthetic organisms (animals, fungi). From the point of view of sterol biosynthesis, C. fasciculata is not related to other ergosterol-synthesising protozoa, such as the hitherto examined phytoflagellates and soil amoebae, which synthesise their sterols via cycloartenol, like photosynthetic organisms (plants, algae).

Inhibition of Cholesterol Biosynthesis in Ovine Ovarian Follicles in vitro by Human Chorionic Gonadotrophin

Abstract: Cholesterol biosynthesis from DL-[2-14C]mevalonic acid ([14C]MVA) was demonstrated in ovine ovarian follicles and isolated thecal tissues and granulosal cells incubated in vitro. Thecal tissues more readily synthesized cholesterol than did granulosal cells when incubated separately, but in the intact follicle the newly synthesized cholesterol distributed evenly between the two tissue layers, indicating that the theca could act as a supplementary source of cholesterol for the granulosal cells. Human chorionic gonadotrophin (hCG) added to the incubation medium was found to inhibit cholesterol biosynthesis from [14C]MVA by intact follicles and isolated thecal tissues, but not granulosal cells. This hCG-induced inhibition was evident in whole follicles incubated for 12--48 h, but not at 3--6 h, and was demonstrated in thecal tissues incubated for 3 h. In all cases where inhibition of cholesterol biosynthesis was observed, 14C label accumulated in a product characterized by thin layer and vapour phase chromatography as lanosterol, implying that the hCG block lies between lanosterol and cholesterol. Treatment of follicles with hCG also reduced the amount of 14C label incorporated into the cholesteryl ester fraction. These changes were accompanied by a corresponding reduction in the tissue content of cholesteryl ester, but there were no changes in the specific activities to indicate that newly synthesized cholesteryl ester was used selectively as a substrate for progestin biosynthesis.

Azole-Resistant Alleles of ERG11 in Candida glabrata Trigger Activation of the Pdr1 and Upc2A Transcription Factors

Abstract: Azoles, the most commonly used antifungal drugs, specifically inhibit the fungal lanosterol α-14 demethylase enzyme, which is referred to as Erg11. Inhibition of Erg11 ultimately leads to a reduction in ergosterol production, an essential fungal membrane sterol. ABSTRACT Azoles, the most commonly used antifungal drugs, specifically inhibit the fungal lanosterol α-14 demethylase enzyme, which is referred to as Erg11. Inhibition of Erg11 ultimately leads to a reduction in ergosterol production, an essential fungal membrane sterol. Many Candida species, such as Candida albicans, develop mutations in this enzyme which reduces the azole binding affinity and results in increased resistance. Candida glabrata is also a pathogenic yeast that has low intrinsic susceptibility to azole drugs and easily develops elevated resistance. In C. glabrata, these azole resistant mutations typically cause hyperactivity of the Pdr1 transcription factor and rarely lie within the ERG11 gene. Here, we generated C. glabrata ERG11 mutations that were analogous to azole resistance alleles from C. albicans ERG11. Three different Erg11 forms (Y141H, S410F, and the corresponding double mutant (DM)) conferred azole resistance in C. glabrata with the DM Erg11 form causing the strongest phenotype. The DM Erg11 also induced cross-resistance to amphotericin B and caspofungin. Resistance caused by the DM allele of ERG11 imposed a fitness cost that was not observed with hyperactive PDR1 alleles. Crucially, the presence of the DM ERG11 allele was sufficient to activate the Pdr1 transcription factor in the absence of azole drugs. Our data indicate that azole resistance linked to changes in ERG11 activity can involve cellular effects beyond an alteration in this key azole target enzyme. Understanding the physiology linking ergosterol biosynthesis with Pdr1-mediated regulation of azole resistance is crucial for ensuring the continued efficacy of azole drugs against C. glabrata.

The oxidosqualene cyclase from the oomycete Saprolegnia parasitica synthesizes lanosterol as a single product.

Abstract: The first committed step of sterol biosynthesis is the cyclisation of 2,3-oxidosqualene to form either lanosterol or cycloartenol. This is catalyzed by an oxidosqualene cyclase. Lanosterol and cycloartenol are subsequently converted into various sterols by a series of enzyme reactions. The specificity of the oxidosqualene cyclase therefore determines the final composition of the end sterols of an organism. Despite the functional importance of oxidosqualene cyclases, the determinants of their specificity are not well understood. In sterol-synthesizing oomycetes, recent bioinformatics and metabolite analysis suggest that lanosterol is produced. However, this catalytic activity has never been experimentally demonstrated. Here we show that the oxidosqualene cyclase of the oomycete Saprolegnia parasitica, a severe pathogen of salmonid fish, has an uncommon sequence in a conserved motif important for specificity. We present phylogenetic analysis revealing that this sequence is common to sterol-synthesizing oomycetes, as well as some plants, and hypothesize as to the evolutionary origin of some microbial sequences. We also demonstrate for the first time that a recombinant form of the oxidosqualene cyclase from S. parasitica produces lanosterol exclusively. Our data pave the way for a detailed structural characterization of the protein and the possible development of specific inhibitors of oomycete oxidosqualene cyclases for disease control in aquaculture.