Topic
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.
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TL;DR: The sterol composition of Pneumocystis carinii, an opportunistic pathogen responsible for life-threatening pneumonia in immunocompromised patients, was determined in this paper.
Abstract: The sterol composition of Pneumocystis carinii, an opportunistic pathogen responsible for life-threatening pneumonia in immunocompromised patients, was determined Our purpose was to identify pathway-specific enzymes to impair using sterol biosynthesis inhibitors Prior to this study, cholesterol 15 (ca 80% of total sterols), lanosterol 1, and several phytosterols common to plants (sitosterol 31, 24alpha-ethyl and campesterol, 24alpha-methyl 30) were demonstrated in the fungus In this investigation, we isolated all the previous sterols and many new compounds from P carinii by culturing the microorganism in steroid-immunosuppressed rats Thirty-one sterols were identified from the fungus (total sterol = 100 fg/cell), and seven sterols were identified from rat chow Unusual sterols in the fungus not present in the diet included, 24(28)-methylenelanosterol 2; 24(28)E-ethylidene lanosterol 3; 24(28)Z-ethylidene lanosterol 4; 24beta-ethyllanosta-25(27)-dienol 5; 24beta-ethylcholest-7-enol 6; 24beta-ethylcholesterol 7; 24beta,-ethylcholesta-5,25(27)-dienol 8; 24-methyllanosta-7-enol 9; 24-methyldesmosterol 10; 24(28)-methylenecholest-7-enol 11; 24beta-methylcholest-7-enol 12; and 24beta-methylcholesterol 13 The structural relationships of the 24-alkyl groups in the sterol side chain were demonstrated chromatographically relative to authentic specimens, by MS and high-resolution 1H NMR The hypothetical order of these compounds poses multiple phytosterol pathways that diverge from a common intermediate to generate 24beta-methyl sterols: route 1, 1 --> 2 --> 11 --> 12 --> 13; route 2, 1 --> 2 --> 9 --> 10 --> 13; or 24beta-ethyl sterols: route 3, 1 --> 2 --> 4 --> 6 --> 7; route 4, 1 --> 2 --> 5 --> 8 --> 7 Formation of 3 is considered to form an interrupted sterol pathway Taken together, operation of distinct sterol methyl transferase (SMT) pathways that generate 24beta-alkyl sterols in P carinii with no counterpart in human biochemistry suggests a close taxonomic affinity with fungi and provides a basis for mechanism-based inactivation of SMT enzyme to treat Pneumocystis pneumonia
15 citations
TL;DR: A CYP51 is cloned and characterized from MAC that functions as a lanosterol 14alpha-demethylase, and the direct interactions of azoles with purified MAC-CYP51 are shown by absorbance and electron paramagnetic resonance spectroscopy.
Abstract: Mycobacterium avium complex (MAC) causes chronic lung disease in immunocompetent people and disseminated infection in patients with AIDS. MAC is intrinsically resistant to many conventional antimycobacterial agents, it develops drug resistance rapidly to macrolide antibiotics, and patients with MAC infection experience frequent relapses or the inability to completely eradicate the infection with current treatment. Treatment regimens are prolonged and complicated by drug toxicity or intolerances. We sought to identify biochemical pathways in MAC that can serve as targets for novel antimycobacterial treatment. The cytochrome P450 enzyme, CYP51, catalyzes an essential early step in sterol metabolism, removing a methyl group from lanosterol in animals and fungi, or from obtusifoliol in plants. Azoles inhibit CYP51 function, leading to an accumulation of methylated sterol precursors. This perturbation of normal sterol metabolism compromises cell membrane integrity, resulting in growth inhibition or cell death. We have cloned and characterized a CYP51 from MAC that functions as a lanosterol 14α-demethylase. We show the direct interactions of azoles with purified MAC-CYP51 by absorbance and electron paramagnetic resonance spectroscopy, and determine the minimum inhibitory concentrations (MICs) of econazole, ketoconazole, itraconazole, fluconazole, and voriconazole against MAC. Furthermore, we demonstrate that econazole has a MIC of 4 μg/ml and a minimum bacteriocidal concentration of 4 μg/ml, whereas ketoconazole has a MIC of 8 μg/ml and a minimum bacteriocidal concentration of 16 μg/ml. Itraconazole, voriconazole, and fluconazole did not inhibit MAC growth to any significant extent.
15 citations
01 Jan 1962
TL;DR: The chapter describes the syntheses of biologically important steroids with an emphasis on the steps where oxygenases take part and some generalizations can be made concerning oxygenases that act on steroids.
Abstract: Publisher Summary Lipids are a class of compounds composed of many and diverse members. Among these, only the group of fatty acids and steroids, which comprise the sterols, bile acids, sex hormones, and adrenal cortical hormones, provide substrates for oxygenase activity. This chapter discusses the oxygenases in lipid and steroid metabolism. Only three oxygenases were found in the fatty acid category: (1) lipoxidase, which performs the hydroperoxidation of unsaturated fatty acids, (2) long chain fatty acid peroxidase, which catalyzes the α-oxidation and decarboxylation of C12–C18 fatty acids, and (3) a fatty acid hydroxylase, which initiates a two-step reaction resulting in the formation of a monounsaturated fatty acid. Some generalizations can be made concerning oxygenases that act on steroids. In the biosynthesis of cholesterol from acetate and its multiples, hydroxylases do not participate until the conversion of the squalene chain to lanosterol. The chapter describes the syntheses of biologically important steroids with an emphasis on the steps where oxygenases take part.
15 citations
TL;DR: At elevated temperature (40 degrees), de novo synthesis of squalene and sterois in the aerated yeast was only 32-35% of that at lower temperature (20 degrees or 30 degrees), and this decrease was attributed to the repression of the enzymes involved in the synthesis of mevalonate from acetyl-COA.
Abstract: Anaerobically grown Saccharomyces cerevisiae was aerated for 7 hr at 20 degrees, 30 degrees, or 40 degrees, in a phosphate buffer containing 2% glucose. At elevated temperature (40 degrees), de novo synthesis of squalene and sterois in the aerated yeast was only 32-35% of that at lower temperature (20 degrees or 30 degrees), and this decrease was attributed to the repression of the enzymes involved in the synthesis of mevalonate from acetyl-COA. In addition, at elevated temperature, the metabolic flux from squalene to ergosterol was blocked at squalene epoxidation, lanosterol demethylation, and ergosta-5, 7, 22, 24(28)-tetraene-3beta-ol reduction.
15 citations
01 Jan 1993
TL;DR: This result shows that ignosterol is able to efficiently replace ergosterol as bulk membrane component and that the fen1-1 mutation eliminates the specific ergostol requirement in yeast.
Abstract: Screening for resistance to fenpropimorph was under- taken in order to isolate yeast mutants affected in the regulation of the ergosterol pathway. Among the mutants isolated, one bearing the recessive fen1-1 mutation was characterized by a 1.~fold increase in the ergosterol level and a general resistance to sterol biosynthesis inhibitors. The fenl-I mutation was linked to MATlocus on chromo some III. The measurement of enzyme activities involved in the ergosterol pathway revealed that isopenteuyl di- phosphate (IPP) isomerase activity was specifically in- creased 1.5~fold as compared to the wild type strain. However, overexpression of IPP isomerase in the wild type strain was not by itself sufficient to lead to sterol increase or resistance to sterol biosynthesis inhibitors, showing that IPP isomerase is not a limiting step in the pathway. The fen1-1 mutation permits viability in aerc~ biosis of yeast disrupted for sterol-14 reductase in absence of exogenous ergosterol supplementation, whereas the co~ responding strain bearing the wild type FEN1 allele grows only in anaerobiosis. This result shows that ignosterol is able to efficiently replace ergosterol as bulk membrane component and that the fen1-1 mutation eliminates the specific ergosterol requirement in yeast. Lipids 28, 907-912 (1993). The sterol biosynthetic pathway is the target of power- ful fungicides. Among them, the most commonly used against pathogenic fungi are azoles and morpholine derivatives. Azoles, such as ketoconazole, flusilazol or LAB 170250 F, inhibit the C-14 lanosterol demethylase step (1-3) through the binding of the fungicide's hetero- cyclic nitrogen atom to the protohaem iron of cytochrome P450 lanosterol demethylase (4). Morpholines block two later steps downstream in the ergosterol pathway, /114 sterol reductase and As-h 7 sterol isomerase (5). These compounds, which are likely to be protonated at physio- logical pH, share some structural and electronic similari- ties with the sterol carbocationic high energy intermedi- ates involved in the A
15 citations