Inhibitory Effect of 15-Oxygenated Sterols on Cholesterol Synthesis from 24,25-Dihydrolanosterol

Morisaki, Masuo; Sonoda, Yoshiko; Makino, Tomomi; Ogihara, Noriko; Ikekawa, Nobuo; Satō, Yoshihiro

doi:10.1093/oxfordjournals.jbchem.a135516

Cited by 20 publications

(7 citation statements)

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“…The organic layer strongly inhibited cholesterol biosynthesis from acetate. Similar or identical oxygenated lanosteroids had been previously reported in Gl [38-42], and found to inhibit conversion of 24,25-dihydrolanosterol to cholesterol at the lanosterol 14 α-demethylase step [49-51], and also indirectly to inhibit HMG-CoA reductase activity [51]. The fact that the aqueous phase from Gl was ineffective at inhibiting cholesterol synthesis (ID 50 > 330) suggests that hydrophilic molecules such as glucans and fibers in Gl do not affect conversion of acetate to cholesterol.…”

Section: Discussionsupporting

confidence: 68%

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et al. 2004

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IntroductionThere has been renewed interest in mushroom medicinal properties. We studied cholesterol lowering properties of Ganoderma lucidum (Gl), a renowned medicinal species.ResultsOrganic fractions containing oxygenated lanosterol derivatives inhibited cholesterol synthesis in T9A4 hepatocytes. In hamsters, 5% Gl did not effect LDL; but decreased total cholesterol (TC) 9.8%, and HDL 11.2%. Gl (2.5 and 5%) had effects on several fecal neutral sterols and bile acids. Both Gl doses reduced hepatic microsomal ex-vivo HMG-CoA reductase activity. In minipigs, 2.5 Gl decreased TC, LDL- and HDL cholesterol 20, 27, and 18%, respectively (P < 0.05); increased fecal cholestanol and coprostanol; and decreased cholate.ConclusionsOverall, Gl has potential to reduce LDL cholesterol in vivo through various mechanisms. Next steps are to: fully characterize bioactive components in lipid soluble/insoluble fractions; evaluate bioactivity of isolated fractions; and examine human cholesterol lowering properties. Innovative new cholesterol-lowering foods and medicines containing Gl are envisioned.

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Section: Discussionsupporting

confidence: 68%

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et al. 2004

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“…Contrary to azole derivatives sterols would have longer life-time in water solution and better membrane permeability. Attempts to use CYP51 substrate analogs to block cholesterol biosynthesis in humans have described that 7-oxo, 15-keto, 15-oxime, 15-hydroxy, 26-oxo derivatives of lanosterol are effective [24,[75][76][77]; derivatives of the 14α-carboaldehyde intermediate of lanosterol are known as hypocholesterolemic agents having dual effect in vivo (competitive CYP51 inhibitors and suppressors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase) [76][77][78]. Finally, 14α-aminoderivatives of lanosterol were found effective to inhibit C. albicans and T. cruzi CYP51 orthologs [36,79].…”

Section: Inhibition Of Cyp51mentioning

confidence: 99%

Sterol 14α-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms

Lepesheva

Waterman

2007

Biochimica et Biophysica Acta (BBA) - General Subjects

408

331

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SummaryThe CYP51 family is an intriguing subject for fundamental P450 structure/function studies and is also an important clinical drug target. This review updates information on the variety of the CYP51 family members, including their physiological roles, natural substrates and substrate preferences, and catalytic properties in vitro. We present experimental support for the notion that specific conserved regions in the P450 sequences represent a CYP51 signature. Two possible roles of CYP51 in P450 evolution are discussed and the major approaches for CYP51 inhibition are summarized.Keywords sterol 14α-demethylase (CYP51); sterol biosynthesis; substrate preferences; catalytic activity; inhibition Family overviewSterol 14α-demethylation as a general part of sterol biosynthetic pathways in eukaryotes [1] has been known and studied for more than 30 years [2][3][4][5][6][7]. The enzyme catalyzing this reaction was first purified from yeast in 1984 (Sacharomyces cerevisiea [8]), and following determination of its primary structure [9] the cytochrome P450 sterol 14α-demethylases were placed into the CYP51 family, a number reserved for fungal sequences [10]. In 1986 the orthologous mammalian P450 was purified from rat liver microsomes [11], in 1996 the first sterol 14α-demethylase was found in plants (Sorghum bicolor [12]), and in 2000 the orthologous nature of a CYP51-like gene [13] from Mycobacterium tuberculosis to eukaryotic CYP51s was confirmed [14].Currently the CYP51 family joins proteins found in 82 organisms from all biological kingdoms. In addition, several plants and fungi contain multiple CYP51 genes (e.g. rice (10), black oats (2), tobacco (2), Arabidopsis thaliana (2), Fuzarium graminearum (3) or Aspergillus species: A. fumigatus (2), A.nidulans (2), A. orizae (3)). As a result, the number of known CYP51 sequences exceeds 100. The reasons for the existence of homologous CYP51 genes in the same species or their precise functions remain unknown, though it was reported that only one of the two CYP51 genes from A. thaliana (CYP51A2) is functional, while the other is an expressed pseudogene [15]. Mammalian genomes contain only one CYP51 gene yet sometimes † Corresponding author: Michael R. Waterman, Tel.: 615-343-1373; Fax: 615-322-4349; E-mail: michael.waterman@vanderbilt.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The average amino acid sequence identity in the CYP51 family is about 30%, varying from relatively high between the proteins from evolutionary closely related species (e.g. 95% in mammals) to lower values within the highly diverse kingdoms of lower...

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“…Mevalonate is a common precursor of all isoprenoids, including sterols, ubiquinones, dolichol, and isopentenyladenine, and blocking mevalonate formation may induce undesired side effects in addition to inhibition of sterol synthesis (16). Therefore, it became necessary to find a new hypolipidemic agent to avoid the adverse effects of mevalonate depletion by lovastatin.…”

mentioning

confidence: 99%

Effect of 26-Oxygenosterols from Ganoderma lucidum and Their Activity as Cholesterol Synthesis Inhibitors

Hajjaj

Macé

Roberts

et al. 2005

Appl Environ Microbiol

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Ganoderma lucidum is a medicinal fungus belonging to the Polyporaceae family which has long been known in Japan as Reishi and has been used extensively in traditional Chinese medicine. We report the isolation and identification of the 26-oxygenosterols ganoderol A, ganoderol B, ganoderal A, and ganoderic acid Y and their biological effects on cholesterol synthesis in a human hepatic cell line in vitro. We also investigated the site of inhibition in the cholesterol synthesis pathway. We found that these oxygenated sterols from G. lucidum inhibited cholesterol biosynthesis via conversion of acetate or mevalonate as a precursor of cholesterol. By incorporation of 24,25-dihydro-[24,25-3 H 2 ]lanosterol and [3-3 H]lathosterol in the presence of ganoderol A, we determined that the point of inhibition of cholesterol synthesis is between lanosterol and lathosterol. These results demonstrate that the lanosterol 14␣-demethylase, which converts 24,25-dihydrolanosterol to cholesterol, can be inhibited by the 26-oxygenosterols from G. lucidum. These 26-oxygenosterols could lead to novel therapeutic agents that lower blood cholesterol.

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Inhibitory Effect of 15-Oxygenated Sterols on Cholesterol Synthesis from 24,25-Dihydrolanosterol

Cited by 20 publications

References 0 publications

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Sterol 14α-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms

Effect of 26-Oxygenosterols from Ganoderma lucidum and Their Activity as Cholesterol Synthesis Inhibitors

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