Showing papers on "Lanosterol published in 1991"
102 citations
TL;DR: The metabolite is efficiently converted to the demethylated delta 8,14-diene sterol in the absence of molecular oxygen or NADPH, thus supporting its identity as the final oxidized intermediate in the lanosterol 14 alpha-methyl demethylase cascade.
100 citations
TL;DR: The results of an accompanying study of the ultrastructural alterations induced by the drug strongly support the notion that ICI 195, 739 acts on T. cruzi by a novel combination of biochemical and cellular effects, which could explain its extraordinary potency in vivo against the parasite.
Abstract: The in vitro antiproliferative effects of ICI 195,739, a recently developed bis-triazole derivative (T. Boyle, D. J. Gilman, M. B. Gravestock, and J. M. Wardleworth, Ann. N.Y. Acad. Sci. 544:86-100, 1988; J. F. Ryley, S. McGregor, and R. G. Wilson, Ann. N.Y. Acad. Sci. 544:310-328, 1988), on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi and some aspects of its mechanism of action are described. Despite previous claims that triazole compounds act on susceptible organisms by essentially the same mechanism demonstrated for the imidazole compounds, i.e., by interfering with the synthesis of ergosterol at the level of the cytochrome P-450-dependent C-14 demethylation of lanosterol, our results indicate that ICI 195,739 acts on T. cruzi epimastigotes by a dual mechanism which involves blockade of ergosterol byosynthesis and a second, still-unidentified target whose alteration leads to immediate growth arrest. Although ICI 195,739 blocks ergosterol biosynthesis at the level of C-14 lanosterol demethylation, as shown by gas-liquid and thin-layer chromatography, growth arrest in ICI 195,739-treated cells is not related to the depletion of the endogenous ergosterol pool, contrary to what was previously found for ketoconazole, the reference compound among antifungal and antiprotozoal azole derivatives. Consistent with this observation is the fact that the concentration of ICI 195,739 required to inhibit de novo synthesis of ergosterol in epimastigotes by 50% is 60 nM, which is essentially identical to that previously found for ketoconazole under identical conditions, while the minimum concentration required to produce complete growth inhibition is 0.1 microM, which is 300 times lower than that of ketoconazole. With respect to the intracellular amastigote form proliferating inside vertebrate (Vero) cells, 10 nM is sufficient to eradicate the parasite completely in 96 h, with no effects on the host cells; this concentration is identical to that previously found for ketoconazole. Growth inhibition and morphological alterations induced by ketoconazole can be reserved by exogenously added ergosterol but not by cholesterol; for ICI 195, 739, neither sterol is capable of reserving the drug effects. Contrary to what was observed for ketoconazole, the in vitro antiproliferative effects of ICI 195, 739 on both forms of the parasite are not potentiated by the simultaneous presence of terbinafine, an allylamine which blocks ergosterol production by the parasite at a different level of the sterol biosynthetic pathway. These results, together with those of an accompanying study of the ultrastructural alterations induced by the drug, strongly support the notion that ICI 195, 739 acts on T. cruzi by a novel combination of biochemical and cellular effects, which could explain its extraordinary potency in vivo against the parasite.
47 citations
41 citations
TL;DR: Findings suggest that upon inhibition of 14 alpha DM by SKF 104976, a mevalonate-derived precursor regulates HMGR activity, even when the sterol synthetic rate is considerably reduced and when HMGR protein levels are very high.
33 citations
29 citations
TL;DR: Different substrate specificities between the yeast and the mammalian 14a-demethylases may reflect certain evolutional alteration in their active sites in relation to the difference in their sterol biosynthetic pathways.
29 citations
TL;DR: Squalene-2,3-epoxide: lanosterol cyclase was purified from rat liver in five steps as a soluble and homogeneous protein and showed a single band on SDS-polyacrylamide gel electrophoresis with a molecular weight of 75 kD.
Abstract: Squalene-2, 3-epoxide : lanosterol cyclase was purified from rat liver in five steps as a soluble and homogeneous protein. The purified enzyme showed a single band on SDS-polyacrylamide gel electrophoresis with a molecular weight of 75 kD. In its native state it behaved as a homo-dimer. The isoelectric point of 5.5 and the apparent Km value for (&3S)-squalene-epoxide of 55 μM were estimated for the cyclase.
27 citations
TL;DR: Direct enzymatic cyclization of squalene oxide to cycloartenol has now been demonstrated in eight algal phyla, whereas five species of dinoflagellates produced lanosterol, representing evidence against an assumed biochemical linkage between photosynthesis and cyclOartenol production from squalenes oxide.
26 citations
TL;DR: Although lanosterol appeared to be capable of modulating cell membrane physical properties it is less effective than cholesterol when growth rates were correlated with NMR parameters, it was found that the membranes of faster growing cells were also more ordered.
24 citations
TL;DR: In this article, the 14 alpha-demethylation of 24,25-dihydrolanosterol (DHL) derivatives having trimmed side chains, 27-nor-DHL, 26,27-dinor, DHL, 25,26-27-trinor-dHL, 24,26,27,tetranor-Dhl, 23,24,25,26-, 27-pentanor-, DHL and 22,23,24-26,26)-hexanor-derivatives were studied with the reconst
TL;DR: It is likely that all sponges are capable of de novo sterol biosynthesis, based on work with radiolabeled lanosterol, cycloartenol, mevalonate and acetate.
Abstract: 1. 1. De novo sterol biosynthesis in the sponges Tethya aurantia and Aplysina fistularis was investigated, using sodium [5,5- 3 H]-mevalonate, [1- 3 H]-farnesol and [3- 3 H]-Squalene was found to be the best precursor for demonstrating de novo sterol biosynthesis in a wider range of sponges. 2. 2. By feeding [3- 3 H]-squalene and using cell-free techniques, the de novo sterol biosynthesis was established in 18 sponges belonging to nine orders. Among these sponges were Axinella polypoides and Axinella verrucosa which had previously been thought to be incapable of de novo sterol biosynthesis based on work with radiolabeled lanosterol, cycloartenol, mevalonate, and acetate. 3. 3. In contrast to earlier assumption, it is likely that all sponges are capable of de novo sterol biosynthesis.
TL;DR: The triazole antifungal agent, ICI 153,066, acts on Candida albicans and Trichophyton quinckeanum by inhibiting demethylation of the sterol ring, which leads to inhibition of the transport of amino acids into the yeasts which probably resulted from alterations in the membrane bound permeation systems.
Abstract: The triazole antifungal agent, ICI 153,066, acts on Candida albicans and Trichophyton quinckeanum by inhibiting demethylation of the sterol ring. In C. albicans this is at the level of lanosterol whereas in T. quinckeanum it is at the level of 24-methylene lanosterol. Inhibition of the demethylation system was shown to be non-competitive, the Vmax of the enzyme was reduced rather than affinity for the substrate lanosterol. The changes in the sterols of C. albicans lead to inhibition of the transport of amino acids into the yeasts which probably resulted from alterations in the membrane bound permeation systems. The reduction in uptake of amino acids was shown to reflect a change in the velocity of transport rather than the affinity of the amino acids for the transport systems.
TL;DR: When reconstituted with NADPH-cytochrome P-450-reductase, the enzyme showed a high activity for lanosterol and 24,25-dihydrolanosterol 14 alpha-demethylation.
TL;DR: Partial (120-fold) purification of oxidosqualene-lanosterol cyclase from yeast is described, finding that the enzyme derived from the microsomal fraction converts 1 mM S-squalene oxide to lanosterol in 5 h and has a pH optimum lower than that of the hog-liver cyclase catalyzing the same reaction.
TL;DR: Results using a radio-high performance liquid chromatography (HPLC) assay show that in rat liver microsomal preparations, with [24,25-3H]dihydrolanosterol as substrate, the compounds do indeed inhibit the biosynthesis of sterols downstream from lanosterol.
TL;DR: Neomycin and a benzodiazepine derivative (RO16-0521) inhibit similarly cholesterol absorption in man but the serum cholesterol level is reduced only by neomycin, and Ketoconazole inhibits 14α-demethylation of lanosterol so that cholesterol synthesis is reduced.
Abstract: Neomycin and a benzodiazepine derivative (RO16-0521) inhibit similarly cholesterol absorption in man but the serum cholesterol level is reduced only by neomycin. Reason(s) for the difference are unknown. Ketoconazole inhibits 14α-demethylation of lanosterol so that cholesterol synthesis is reduced. The agent inhibits also cholesterol absorption. The serum cholesterol level is reduced by about 20%, the lowering being potentiated by a simultaneous cholestyramine treatment.
Patent•
05 Mar 1991TL;DR: In this article, the authors used substituted 15-oxa-, 15-thia-, and 15-aza-dihydrolanosterols to suppress the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), an enzyme which is important in cholesterol biosynthesis.
Abstract: The present invention relates to novel substituted 15-oxa-, 15-thia-, and 15-aza-dihydrolanosterols, to pharmaceutical compositions containing such compounds, and to methods of using these compounds to suppress the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), an enzyme which is important in cholesterol biosynthesis. The overall effect of these heterocyclic lanosterol analogs is to decrease cholesterol formation, thereby resulting in lower serum cholesterol levels in mammals, and impaired ergosterol synthesis in fungi.
TL;DR: DNA sequencing and analysis of genomic DNA using the polymerase chain reaction were used to demonstrate that SOD1 and ERG11 are adjacent genes in Saccharomyces cerevisiae S288c and to establish the correct intergenic sequence of this segment on chromosome VIII.
Abstract: DNA sequencing and analysis of genomic DNA using the polymerase chain reaction were used to demonstrate that SOD1 and ERG11 are adjacent genes in Saccharomyces cerevisiae S288c and to establish the correct intergenic sequence of this segment on chromosome VIII.
TL;DR: The presence of this enzyme in microsomes from various human tissues suggests that it may play a role in cellular regulation of cholesterol synthesis, and in particular the conversion of dihydrolanosterol to oxylanosterol intermediates and the diene.
TL;DR: In this article, the authors synthesized 2,3-Epoxysqualene and its racemate by two convenient routes, and the products have the label in a metabolically-nonlabile position relative to the demethylation of lanosterol to cholesterol.
Abstract: [24,30-14C]-(3S)-2,3-Epoxysqualene and its racemate were synthesized by two convenient routes. The products have the label in a metabolically-nonlabile position relative to the demethylation of lanosterol to cholesterol.
TL;DR: Using a tritium release assay, the sensitivity required to characterize (3β)-32-(ethynyl)lanost-8-en-3-ol (1) as a time-dependent irreversible inhibitor of sterol 14α-demethylase is attained.
TL;DR: In this article, the structure of the major metabolites of 7,11-dioxodihydrolanosterol has been determined using 2D-NMR and showed that the tetracyclic skeleton can undergo regioselective oxidation-reduction modifications at the 3 and 7 positions.
Abstract: While mycobacteria are unable to degrade lanosterol and dihydrolanosterol, principal components of wool fat, we observed the transformation of some of their autoxidation products by Mycobacterium phlei. By analogy with the mechanism of degradation of cholesterol, this difference was assumed to be due to the requirement for the presence of an enone group before the side-chain can be degraded. This paper reports the spectroscopic determination of the structure of the major metabolites of 7,11-dioxodihydrolanosterol. The side-chain is degraded from eight carbon atoms to three, the terminal carbon atom being oxidized to a primary alcohol or a methyl ester. The tetracyclic skeleton can undergo regioselective oxidation–reduction modifications at the 3- and 7-position. Their conformational analysis, carried out by 2D-NMR methods, indicates a chair form for ring A of 3β-hydroxy derivatives, while it is highly deformed for 3-keto compounds as predicted formerly by Mislow for this lanostane series.
TL;DR: In vitro antitumor activity testing of the lanosterol derivatives revealed that 3 beta-hydroxylanost-7-en-32-oic acid has antineoplastic activity.
Abstract: Lanosterol derivatives with a functional group at C-32 have been synthesized from 3 beta-acetoxylanostan-7 alpha-ol. The key reaction of the synthesis is the hypoiodite reaction of 3 beta-acetoxylanostan-7 alpha-ol. In vitro antitumor activity testing of the lanosterol derivatives revealed that 3 beta-hydroxylanost-7-en-32-oic acid has antineoplastic activity.
TL;DR: Lanosterol was obtained by adding SSF-109, a sterol biosynthesis inhibitor, to the hepatocytes suspension and the proton-decoupled 13C–1H COSY spectrum confirmed the stereospecific hydrogen attack at C-7, C-15 and C-24.
Abstract: Since isolated dog hepatocytes have been shown to exhibit potent activity for the synthesis of cholesterol from acetic acid, an analysis of cholesterol and lanosterol biosynthesized from [1,2-13C2]- or [2-13C2H3] acetate in fresh isolated hepatocytes has been attempted in order to clarify the incorporation and distribution of the acetate carbon and hydrogen into these sterols. Lanosterol was obtained by adding SSF-109, a sterol biosynthesis inhibitor, to the hepatocytes suspension. 13C NMR spectroscopic analysis of the [13C]- and [13C2H]-labelling patterns of these compounds confirmed the following: (i) the involvement of two 1,2-hydride shifts, 20-H from C-17 and 17-H from C-13; (ii) two 1,2-methyl migrations, 13-methyl group (C-18) from C-14 and 14-methyl group (C-32) from C-8 in the cyclization of 2,3-oxidosqualene to form lanosterol; and (iii) stereospecific hydrogenation from the Si-face at C-25 in the conversion of lanosterol into cholesterol. The proton-decoupled 13C–1H COSY spectrum confirmed the stereospecific hydrogen attack at C-7, C-15 and C-24. The deuterium atoms of [1-2H2]ethanol were incorporated into lanosterol at C-2, C-6, C-11, C-12, C-16 and C-23, which arise from C-5 of mevalonic acid.
TL;DR: Lanosterol 14 alpha-demethylase was found to be specific for lanosterol and did not metabolize a number of P-450 substrates including benzo[a]pyrene, and dibutyryl cyclic AMP did not affect P-45014DM or P- 450 reductase levels.
Abstract: The potential inducibility of the lanosterol 14 alpha-demethylase (P-45014DM) from Saccharomyces cerevisiae Y222 by xenobiotics was investigated. This enzyme and NADPH-cytochrome P-450 reductase were unaffected by a number of compounds known to induce mammalian and some yeast cytochrome P-450 monooxygenases. Furthermore, dibutyryl cyclic AMP did not affect P-45014DM or P-450 reductase levels, while growth at 37 degrees C resulted in a slight decrease. P-45014DM was found to be specific for lanosterol and did not metabolize a number of P-450 substrates including benzo[a]pyrene.
Patent•
12 Sep 1991
TL;DR: In this article, a dermal medicine is obtained by blending a higher fatty acid lanosterol ester with a system containing a phospholipid or a glycolipid and a high fatty acid cholestercol ester.
Abstract: PURPOSE:To produce a dermal medicine for external use, more excellent in improvement of roughness of the skin by blending a higher fatty acid lanosterol ester with a system containing a phospholipid or a glycolipid and a higher fatty acid cholestercol. ester. CONSTITUTION:A dermal medicine excellent in utility for the skin and obtained by blending a higher fatty acid lanosterol ester such as lanosterol oleate with a dermal medicine for external use containing one or more kinds of substances selected from a phospholipid such as soybean lecithin or yolk lecithin and a glycolipid such as cerebroside and a higher fatty acid cholesterol ester such as cholesterol oleate.
TL;DR: In this paper, the synthesis of cycloprotobuxine-A (5),representative of Buxus alkaloids, and its two isomeric alkaloid with 3β,20R- and 3α, 20R-configuration, from lanosterol, is described.