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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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Journal ArticleDOI
Yuko Aoki1, F Yoshihara1, M Kondoh1, Y Nakamura1, Noboru Nakayama1, Mikio Arisawa1 
TL;DR: Ro 09-1470 preferentially inhibited the yeast P-450(14DM), showing a 50% inhibitory concentration (IC50) of 0.47 to approximately 1.1 microM, which is much lower than the IC50s for rat hepatic P- 450s catalyzing cholesterol biosynthesis, p-nitroanisol O-demethylation, aniline hydroxylation, and aminopyrine N-dem methylation.
Abstract: Ro 09-1470 is a new antifungal agent that belongs to a series of compounds characterized by a tetrahydropyran skeleton with glycine and alkenyl side chains and that inhibits P-450 lanosterol C-14 demethylase (P-450(14DM)) of fungi (Y. Aoki, T. Yamazaki, M. Kondoh, Y. Sudoh, N. Nakayama, Y. Sekine, H. Shimada, and M. Arisawa, J. Antibiot. 45:160-170, 1992; S. Matsukuma, T. Ohtsuka, H. Kotaki, H. Sawairi, T. Sano, K. Watanabe, N. Nakayama, Y. Itezono, M. Fujiu, N. Shimma, K. Yokose, and T. Okuda, J. Antibiot. 45:151-159, 1992). We have studied the compound9s mode of interaction with fungal P-450(14DM) and its selectivity for the fungal versus mammalian P-450 enzymes. Ro 09-1470 bound to the Saccharomyces cerevisiae P-450(14DM) by coordinating to the heme with one-to-one stoichiometry. Unlike the azole compounds, it interacted with both ferric and ferrous heme. It was active also against the P-450(14DM) of Candida albicans. Ro 09-1470 preferentially inhibited the yeast P-450(14DM), showing a 50% inhibitory concentration (IC50) of 0.47 to approximately 1.1 microM, which is much lower than the IC50s for rat hepatic P-450s catalyzing cholesterol biosynthesis (IC50 = 341 microM), p-nitroanisol O-demethylation (> 1,000 microM), aniline hydroxylation (> 1,000 microM), and aminopyrine N-demethylation (920 microM). The degree of selectivity for yeast P-450 was higher than that of ketoconazole.

18 citations

Journal ArticleDOI
TL;DR: The biochemical lesion of mutant 215, a cholesterol-requiring Chinese hamster ovary cell auxotroph isolated and partially characterized previously, was localized at the 4 alpha-methylsterol oxidase enzyme system, suggesting that the enzyme systems responsible for 4alpha-methyl- and 4,4-dimethylsterols may share a common component.
Abstract: Sensitive in vitro lanosterol 14 alpha- and 4 alpha-methylsterol oxidase assays, particularly suitable for cell extracts of tissue culture cells, were developed and validated. Using these assays, we showed that the biochemical lesion of mutant 215, a cholesterol-requiring Chinese hamster ovary cell auxotroph isolated and partially characterized previously [Chang, T. Y., Telakowski, C., Vanden Heuvel, W., Alberts, A. W., & Vagelos, P. R. (1977) Proc. Natl. Acad. Sci. U.S.A. 74, 832-836], was localized at the 4 alpha-methylsterol oxidase enzyme system. The defect in 4 alpha-methylsterol oxidase activity in mutant 215 cells could be demonstrated by using either 4,4-dimethylcholestanol or 4 alpha-methylcholestanol as the substrate, suggesting that the enzyme systems responsible for 4 alpha-methyl- and 4,4-dimethylsterols may share a common component. However, demethylation of the C-14 alpha methyl group was found to occur at identical rates in wild-type and mutant 215, suggesting that C-14 alpha demethylation and C-4 alpha demethylation may occur by separate enzyme systems. A [3H]dihydrolanosterol incorporation experiment in intact cells of wild-type and mutant 215 supported these conclusions. Despite these results, a [14C]acetate pulse experiment indicated that [14C]lanosterol, instead of its 14C-labeled 14-demethylated sterol derivative(s), accumulated in intact cells of mutant 215. Possible implications of these findings for the mechanisms of lanosterol demethylation reactions are discussed.

18 citations

Journal ArticleDOI
TL;DR: It is suggested that the product specificity of OSC is likely to be controlled by kinetics, rather than thermodynamics, as the precursor of lanosterol is in fact not the most stable cationic intermediate for wild-type OSC.
Abstract: Oxidosqualene-lanosterol cyclase (OSC) is a key enzyme in the biosynthesis of cholesterol. The catalytic mechanism and the product specificity of OSC have herein been studied using QM/MM calculations. According to our calculations, the protonation of the epoxide ring of oxidosqualene is rate-limiting. Wild-type OSC (which generates lanosterol), and the mutants H232S (which generates parkeol) and H232T (which generates protosta-12,24-dien-3-β-ol) were modeled, in order to explain the product specificity thereof. We show that the product specificity of OSC at the hydride/methyl-shifting stage is unlikely to be achieved by the stabilization of the cationic intermediates, as the precursor of lanosterol is in fact not the most stable cationic intermediate for wild-type OSC. The energy barriers for the product-determining conversions are instead found to be related to the product specificity of different OSC mutants, and we thus suggest that the product specificity of OSC is likely to be controlled by kinetics, rather than thermodynamics.

18 citations

Journal ArticleDOI
TL;DR: It is revealed that synthetic lanosterol analogues could reverse multiple types of mutant-crystallin aggregates in cell models with excellent potency and efficacy and can improve the viability of the HLE-B3 cell line.
Abstract: We describe here the development of potent synthetic analogues of the naturally occurring triterpenoid lanosterol to reverse protein aggregation in cataracts. Lanosterol showed superiority to other scaffolds in terms of efficacy and generality in previous studies. Various modified lanosterol derivatives were synthesized via modification of the side chain, ring A, ring B, and ring C. Evaluation of these synthetic analogues draws a clear picture for SAR. In particular, hydroxylation of the 25-position in the side chain profoundly improved the potency, and 2-fluorination further enhanced the biological activity. This work also revealed that synthetic lanosterol analogues could reverse multiple types of mutant-crystallin aggregates in cell models with excellent potency and efficacy. Notably, lanosterol analogues have no cytotoxicity but can improve the viability of the HLE-B3 cell line. Furthermore, representative compound 6 successfully redissolved the aggregated crystallin proteins from the amyloid-like fib...

18 citations

Journal ArticleDOI
TL;DR: The localization of tritium labelled cholesterol, sitosterol, and lanosterol in chicken tissues by chemical means and autoradiographic technique is the basis of this report.
Abstract: THERE is an increasing accumulation of evidence that mammalian enzyme systems are capable of transforming sterols other than cholesterol. ROSENHEIM and W E B S T E ~ S (1941) isolation of a hydrogenated product (coprositostanol) from the faeces of rats fed sitosterol indicated some degree of metabolic conversion. More recently the conversion of sitosterol to cortisol was demonstrated in the guinea pig (WERRIN, CHAIKOFI: and JONES, 1960). Ergosterol was converted to acidic products by the rat (HANAHAN and AL-WAKIL, 1953) and guinea pig (GLOVER, LEAT and MORTON, 1957). The sterol oxidase system of rat liver mitochondria (WHITEHOUSE, STAPLE and GURIN, 1959) was found to convert ergosterol (KRITCHEVSKY, STAPLE and WHITEHOUSE, l961), desmosterol (KRITCHEVSKY and STAPLE, 1962) and other sterols such as cholestenone and cholestanol (STEVENSON and STAPLE, 1961) to products identical with, or closcly resembling, bile acids. DAVISON and his collaborators (DAVISON and WAJDA, 1959; DAVISON eta/., 1958, 1959) demonstrated that cholesterol injected into very young chickens or rabbits may pcrsist in the nervous system of these animals for considerable lengths of time. Our own interests in the metabolism of cholesterol and related sterols prompted us to compare the distribution and persistence in chicken tissues of cholesterol, sitosterol, and lanosterol. The localization of tritium labelled cholesterol, sitosterol, and lanosterol in chicken tissues by chemical means and autoradiographic technique is the basis of this report. M A T E R I A L S A N D M E T H O D S

18 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202331
202261
202120
202023
201914
201822