Showing papers on "Lanosterol published in 1986"
TL;DR: Data support the conclusion that a single enzyme species is responsible for all three oxidations of the C-32 demethylation sequence, and intermediates which do not routinely accumulate during dem methylation are freely diffusible from the enzyme when appropriate conditions are established to prevent their further metabolism.
91 citations
TL;DR: The hypothesis that a single isozyme of cytochrome P-450 is responsible for all three oxidations and the lyase activity involved in the lanosterol C-32 demethylation sequence is supported.
90 citations
TL;DR: 24,25-epoxylanosterol per se was not an inhibitor of reductase activity but could be metabolized to regulatory polar sterols through a cytochrome P-450 dependent reaction which was sensitive to ketoconazole.
90 citations
TL;DR: It is hypothesized that itraconazole's selective activity on ergosterol bisosynthesis is due to its high affinity for the apoprotein of the C. albicans cyt.
Abstract: The N-substituted triazole, itraconazole, has high affinity for the cytochrome P-450 (cyt. P-450) isozyme involved in the 14α-demethylation of lanosterol in Candida albicans microsomes. Fifty per cent inhibition was already observed at itraconazole concentrations ≤ 5 × 10−9 M. Higher concentrations (≥ 10−7 M) of this antifungal are needed to interfere with the 14 α-demethylation in mammalian cells. Unlike ketoconazole, itraconazole does not significantly affect in vitro androgen, gluco- and mineralocorticoid steroidogenesis. Itraconazole also does not affect the cyt. P-450-dependent 19-hydroxylation of testosterone, a step in the conversion of androgens to estrogens. The 1-hydroxylation of testosterone by pig testes microscomes is only slightly inhibited. It is hypothesized that itraconazole's selective activity on ergosterol bisosynthesis is due to its high affinity for the apoprotein of the C. albicans cyt. P-450 involved in the 14α- demethylation of lanosterol.
88 citations
TL;DR: The ketoconazole-induced alterations in amastigote sterols parallel those previously reported in fungi and L. m.
84 citations
TL;DR: 2-aza-2,3-dihydrosqualene and its derivatives strongly inhibited the cyclases, the site of the enzyme responsible for binding to the inhibitor is quite sensitive to the steric hindrance, and the degree of the inhibitory activity is greater in higher plants than in rat liver or fungi.
Abstract: The 2,3-oxido squalene (SO) cyclases represent a group of enzymes which convert SO into polycyclic triterpenoids such as lanosterol, cycloartenol, cucurbitadienol and beta-amyrin Taking into account the postulated model of the enzymatic cyclization of SO, we have investigated the possibility of designing compounds that would be selective and potent inhibitors of SO cyclases Due to the fundamental role of sterols in animal, higher plant and fungal tissues, these inhibitors might behave as very selective (ipocholesterolemic, antifungal or phytotoxic) drugs Our first approach was the synthesis and biological evaluation of 2-aza-2,3-dihydrosqualene and its derivatives which, being protonated at physiological pH, would present some similarities to the C-2 carbon ion generated by the opening of the oxirane ring of SO Microsomes from different sources (germinated pea cotyledons, maize seedlings, rat liver and yeasts) were utilized to determine the inhibition values (I50: concentration of inhibitor producing 50% inhibition at a given substrate concentration) From the results obtained so far we conclude that 2-aza-2-dihydrosqualene and its derivatives strongly inhibited the cyclases, the site of the enzyme responsible for binding to the inhibitor is quite sensitive to the steric hindrance, and the degree of the inhibitory activity is greater in higher plants than in rat liver or fungi
79 citations
TL;DR: The results are consistent with the earlier suggestion that delta 8(14)-sterols are neither formed nor metabolized by the same microsomal enzymes that catalyze transformation of lanosterol to cholesterol.
55 citations
TL;DR: With [3H-24,25]-dihydrolanosterol as substrate, large-scale metabolic formation of intermediates of lanosterol demethylation was carried out to identify all compounds in the metabolic process and characterized by ultraviolet, 1H-NMR, and infrared spectroscopy of the isolated sterols.
50 citations
TL;DR: It is established that ketoconazole is a potent inhibitor of cholesterol production in vivo and in vitro.
46 citations
TL;DR: The results are interpreted to imply that regulation of sterol C-24 transalkylation may be a mechanism to mediate life cycle events of fungi.
45 citations
TL;DR: For the first time 2,3-oxidosqualene cycloartenol cyclase and β-amyrin cyclase have been differentiated in the same plant material by use of a specific inhibitor.
TL;DR: The effect of the piperazine derivative BM 15.766 on the biosynthesis of sterols was investigated in adult rat hepatocytes in primary monolayer culture, which led to a dose-dependent reduction of cholesterol in the serum of various species of animals such as rat, dog and marmoset.
TL;DR: Two compounds inhibited squalene epoxidase and 2,3‐oxidosqualene cyclase to varying degrees in microsomes from C. albicans and from rat liver and led to accumulation of an unidentified polar product.
TL;DR: Representative members in each of the four orders of Oomycetes have been examined for their ability to synthesize and polycyclize squalene-oxide to a tetracyclic product and to differentiate between cycloartenol and lanosterol metabolism to sterols.
Abstract: Representative members in each of the four orders of Oomycetes (Phytophthora cactorum, Peronosporales;Lagenidium callinectes, L. giganteum, Lagenidiales;Saprolegnia ferax, Saprolegniales;Apodachylella completa, Leptomitales) have been examined for their ability to synthesize and polycyclize squalene-oxide (SO) to a tetracyclic product and to differentiate between cycloartenol and lanosterol metabolism to sterols.P. cactorum andL. giganteum failed to synthesize or metabolize SO, cycloartenol or lanosterol. While the other three fungi synthesized sterols via SO and lanosterol, a minor metabolism of added cycloartenol to the 4,4-desmethyl-14α-methylcyclosteroid dehydropollinastanol was observed.
TL;DR: Observations indicate that the 14 alpha-demethylation of lanosterol by yeast microsomes occurs sequentially via the Trienol, and reduction of the trienol to 4,4-dimethylzymosterol is mediated by an AY-9944-sensitive reductase.
TL;DR: In this article, the tritium exchange-labeling of keto steroids and their subsequent conversion to sterol was used to show that 3H is introduced primarily into positions 2 and 6 ([2,2,4.6-3H]-cholest-5-en-3β-ol) rather than exclusively at 2 and 4 as the literature claims.
Journal Article•
TL;DR: It is suggested that chloroquine at proper doses, in combination with a bile acid-binding resin, might have potential value in the treatment of hypercholesterolemia.
Abstract: Chloroquine is an effective inhibitor of cholesterol synthesis in freshly isolated rat hepatocytes, cultured mouse L cells and 20,000 X g supernatants of mouse liver homogenates. Half-maximal inhibition is found at concentrations ranging from 10 to 30 microM. The drug specifically inhibits 2,3 oxidosqualene cyclase, the enzyme catalysing the conversion of squalene 2,3 oxide into lanosterol. Chloroquine also inhibits the lysosomal hydrolysis of cholesteryl esters, but probably this effect only occurs at somewhat higher concentrations of the drug. It is suggested that chloroquine at proper doses, in combination with a bile acid-binding resin, might have potential value in the treatment of hypercholesterolemia.
TL;DR: It is indicated that NS-1 cells are defective in cholesterol biosynthesis and the site of lesion is identified as the demethylation of lanosterol to C-29 sterol intermediates.
TL;DR: As authentic samples for identification of 29-norlanostane derivatives isolated from plant fossil, 29-lanostan-24-one and -23-one were synthesized from a commercial lanosterol containing dihydrolanosterol as mentioned in this paper.
Abstract: As authentic samples for identification of 29-norlanostane derivatives isolated from plant fossil, 29-norlanostan-24-one and -23-one, 29-norlanost-9(11)-en-24-one, -23-one, and -3-one, 29-norlanost-7-en-3-one, and 29-norlanostan-3-one were synthesized from a commercial lanosterol containing dihydrolanosterol.
TL;DR: The effects of two fungicides, triarimol and tridemorph, on sterol biosynthesis were examined in Achlya americana, Dictyuchus monosporous, Apodachlyella completa, and Lagenidium callinectes, suggesting that the evolution of the Oomycetes from photosynthetic algal ancestors is unkikely.
01 Jan 1986
TL;DR: The effects of prostaglandin E1 on the receptor-mediated accumulation and degradation of [125I] LDL and on the biosynthesis of total sterols, cholesterol and lanosterol from [14C] acetate were studied in freshly isolated human mononuclear leukocytes.
Abstract: The effects of prostaglandin E1 (PGE1) on the receptor-mediated accumulation and degradation of [125I] LDL and on the biosynthesis of total sterols, cholesterol and lanosterol from [14C] acetate were studied in freshly isolated human mononuclear leukocytes. Incubation of cells for 20 h in a medium devoid of lipoprotein increased the specific accumulation and the degradation of [125I] LDL as well as the synthesis of sterols, cholesterol and lanosterol from [14C] acetate. PGE1 added in increasing concentrations to the incubation medium at zero-time inhibited the induction of LDL receptor activity, the suppression of the accumulation being 70% and the degradation of LDL 66% at a concentration of 10 µmol/liter. Also, the biosynthesis of sterols, cholesterol and lanosterol was inhibited by 50%, 61% and 38%, respectively, by the prostaglandin at a concentration of 10 µmol/liter. The action of PGE1 on both LDL receptor activity and sterol synthesis could be mimicked by dibutyryl cAMP.
TL;DR: 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, indicating that this biosynthesis pathway is rather similar to those of other non-photosynthetic organisms (animals, fungi).
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).
TL;DR: It is tentatively suggested that this study provides some evidence that the flexibility of cholesterol synthesis is involved in the responsiveness to dietary cholesterol.
01 Jan 1986
TL;DR: Questions about the role of sterol carrier protein 2 in cellular cholesterol metabolism and its role in cholesterol biosynthesis and esterification in situ were raised by the observation that SCP2 may be secreted by Morris hepatoma cells.
Abstract: Rat liver contains proteins that in vitro modulate microsomal enzymes of cholesterol biosynthesis (for a recent review, see reference 1). One of these cytosolic modulators is sterol carrier protein 2 (SCP2) which stimulates the microsomal conversion of intermediates between lanosterol and cholesterol (2–4). This protein also facilitates net mass transfer of cholesterol between membranes (5–7). Through this action SCP2 stimulates the formation of cholesterol esters by microsomal membranes (6,8,9) and the conversion of cholesterol into pregnenolone by adrenal mitochondria (1,10). However, a recent study with rat hepatocytes and Reuber H35 hepatoma cells failed to provide support for an important role of SCP2 in cholesterol biosynthesis and esterification in situ (11). Additional questions about its role in cellular cholesterol metabolism were raised by the observation that SCP2 may be secreted by Morris hepatoma cells (12).
Journal Article•
TL;DR: 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 as mentioned in this paper.
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).
TL;DR: As authentic samples for identification of 29-norlanostane derivatives isolated from plant fossil, 29-lanostan-24-one and -23-one were synthesized from a commercial lanosterol containing dihydrolanosterol as mentioned in this paper.
Abstract: As authentic samples for identification of 29-norlanostane derivatives isolated from plant fossil, 29-norlanostan-24-one and -23-one, 29-norlanost-9(11)-en-24-one, -23-one, and -3-one, 29-norlanost-7-en-3-one, and 29-norlanostan-3-one were synthesized from a commercial lanosterol containing dihydrolanosterol.