Studies on the 14α‐Demethylation Mechanism in Cholesterol Biosynthesis

Galli‐Kienle, Mariza; Anastasia, Mario; Cighetti, Giuliana; Galli, Giovanni; Fiecchi, Alberto

doi:10.1111/j.1432-1033.1980.tb04844.x

Cited by 10 publications

(8 citation statements)

References 34 publications

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“…The similar phenomenon had been reported that cinnamaldehyde caused several genes involved in cell wall biosynthesis dysfunction 12,24 . Ergosterol is one of the principal sterol ingredients in the fungal membrane and is crucial for survival due to the ability in maintaining cell membrane fluidity, permeability, and pheromone signaling 44–46 . In the present work, the transcriptional level of several genes related ergosterol was down-regulated, for example squalene monooxygenase Erg1 (AFLA_061500), C-14 sterol reductase (AFLA_051080 and AFLA_111350).…”

Section: Discussionmentioning

confidence: 99%

The anti-aflatoxigenic mechanism of cinnamaldehyde in Aspergillus flavus

Wang

Jin

et al. 2019

Sci Rep

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Aflatoxin B 1 (AFB 1 ), the predominant and most carcinogenic naturally polyketide, is mainly produced by Aspergillus flavus and Aspergillus parasiticus . Cinnamaldehyde has been reported for inhibiting the growth and aflatoxin biosynthesis in A. flavus . But its molecular mechanism of action still remains largely ambiguous. Here, the anti-aflatoxigenic mechanism of cinnamaldehyde in A. flavus was investigated via a comparative transcriptomic analysis. The results indicated that twenty five of thirty genes in aflatoxin cluster showed down-regulation by cinnamaldehyde although the cluster regulators aflR and aflS were slightly up-regulated. This may be due to the up-regulation of the oxidative stress-related genes srrA , msnA and atfB being caused by the significant down-regulation of the diffusible factor FluG . Cinnamaldehyde also inhibited aflatoxin formation by perturbing GPCRs and oxylipins normal function, cell wall biosynthesis and redox equilibrium. In addition, accumulation of NADPH due to up-regulation of pentose phosphate pathway drove acetyl-CoA to lipids synthesis rather than polyketides. Both GO and KEGG analysis suggested that pyruvate and phenylalanine metabolism, post-transcriptional modification and key enzymes biosynthesis might be involved in the suppression of AFB 1 production by cinnamaldehyde. This study served to decipher the anti-aflatoxigenic properties of cinnamaldehyde in A. flavus and provided powerful evidence for its use in practice.

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Section: Discussionmentioning

confidence: 99%

The anti-aflatoxigenic mechanism of cinnamaldehyde in Aspergillus flavus

Wang

Jin

et al. 2019

Sci Rep

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“…Previous findings have demonstrated that hepatic microsomes can metabolize 14a-(hydroxymethyl)-5a-cholest-7-en-3/3-ol and 5a-cholest-8-ene-14a-carbaldehyde to demethylated products (Pascal, 1980;Galli-Kienle et al, 1980). Presumably this demethylation reaction is catalyzed by the lanosterol 14a-methyl demethylase.…”

Section: Discussionmentioning

confidence: 99%

Substrate-based inhibitors of lanosterol 14.alpha.-methyl demethylase: I. Assessment of inhibitor structure-activity relationship and cholesterol biosynthesis inhibition properties

Trzaskos¹,

Ko²,

Magolda³

et al. 1995

Biochemistry

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A series of 15-, 32-, and 15,32-substituted lanost-8-en-3 beta-ols is described which function as inhibitors of cholesterol biosynthesis. These agents inhibit lanosterol 14 alpha-methyl demethylase activity as well as suppress HMG-CoA reduction activity in cultured cells. Several of these agents are extremely potent as both demethylase inhibitors and reductase suppressors, while others are more selective in their activities. Selected regio double bond isomers show preference for demethylase inhibition with the following order: delta 8 > delta 7 > delta 6 = unsaturated sterols. Comparisons also show that 4,4-dimethyl sterols are always more potent demethylase inhibitors and reductase suppressors than their 4,4-bisnomethyl counterparts. However, evaluation of an extensive oxylanosterol series leads us to conclude that demethylase inhibition and reductase suppression are not parallel in the same molecule. In addition, the oxylanosterols, but not the oxycholesterols, are able to disrupt coordinate regulation of HMG-CoA reductase from the LDL receptor. Thus, oxylanosterol treatment at levels which suppress reductase activity enhances LDL receptor activity. These results demonstrate that compounds can be made which (1) are selective reductase suppressors enabling dissection of the dual inhibitor nature of these compounds and (2) maximize reductase suppression and LDL receptor induction without demethylase inhibition which could lead to novel agents for serum cholesterol lowering.

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“…5 ␣ -Cholestane and 19-hydroxycholesterol used as internal standards (IS) and BHT were purchased from Sigma Chemical Co. (St. Louis, MO). Deuterated lathosterol was synthesized (15). Silica cartridge columns (Supelclean…”

Section: Methodsmentioning

confidence: 99%

Serum 27-hydroxycholesterol in patients with primary biliary cirrhosis suggests alteration of cholesterol catabolism to bile acids via the acidic pathway

Puppo

Kienle

Petroni

et al. 1998

Journal of Lipid Research

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Reduced cholesterol synthesis has been reported in patients with primary biliary cirrhosis but no data are available on changes in cholesterol catabolism induced by the disease. Serum levels of 7 ␣ -hydroxycholesterol and 27hydroxycholesterol have been measured in 25 patients (either normocholesterolemic or hypercholesterolemic) with primary biliary cirrhosis and in control subjects. To evaluate cholesterol synthesis, serum levels of lathosterol were measured, and campesterol and sitosterol were considered to reflect intestinal absorption and biliary elimination of sterols. In normocholesterolemic patients with primary biliary cirrhosis, lathosterol was significantly lower than in normocholesterolemic controls ( P Ͻ 0.05) whereas no difference was found between hypercholesterolemic patients and hypercholesterolemic controls. Serum concentrations of sitosterol were significantly higher in both normocholesterolemic and hypercholesterolemic patients with primary biliary cirrhosis as compared with the respective controls ( P Ͻ 0.01). In patients with primary biliary cirrhosis, serum 7 ␣hydroxycholesterol was slightly higher than in controls. 27-Hydroxycholesterol was significantly higher in hypercholesterolemic compared to normocholesterolemic controls ( P Ͻ 0.05) and a significant linear correlation ( r ‫؍‬ 0.771; P Ͻ 0.001) was found between 27-hydroxycholesterol and cholesterol. In contrast, in patients with primary biliary cirrhosis, high cholesterol concentrations were not associated with increased serum levels of 27-hydroxycholesterol. Our data confirm that in patients with primary biliary cirrhosis, cholesterol synthesis and biliary elimination of sterols are impaired and also suggest that both the feedback regulation of retained bile acids on cholesterol 7 ␣ -hydroxylase and the scavenger effect on elevated serum cholesterol by cholesterol 27-hydroxylase are deficient in these patients.

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Studies on the 14α‐Demethylation Mechanism in Cholesterol Biosynthesis

Cited by 10 publications

References 34 publications

The anti-aflatoxigenic mechanism of cinnamaldehyde in Aspergillus flavus

The anti-aflatoxigenic mechanism of cinnamaldehyde in Aspergillus flavus

Substrate-based inhibitors of lanosterol 14.alpha.-methyl demethylase: I. Assessment of inhibitor structure-activity relationship and cholesterol biosynthesis inhibition properties

Serum 27-hydroxycholesterol in patients with primary biliary cirrhosis suggests alteration of cholesterol catabolism to bile acids via the acidic pathway

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