Lipids of Candida Albicans
Rajendra Prasad, Mahmoud A. Ghannoum in Lipids of Pathogenic Fungi, 2017
C-14 demethylase is another enzyme that has been widely studied in C. albicans because it is the main target of azoles.59 These antifungals inhibit cytochrome P450-dependent 14α-demethylase, a key enzyme in ergosterol and cholesterol biosynthesis.59-63 The accumulation of methylated sterols as a result of azole action is known to disrupt membrane structure and function. In order to understand the molecular basis of interaction between azoles and C-14 demethylase, it was recently purified from C. albicans.64 The molecular weight of the purified enzyme is estimated to be 51 kDa. Its reconstitution in a model membrane system of dilauroylphosphatidylcholine with NADH and O2 catalyzed the complete 14a-demethylation of lanosterol, which was inhibited by carbon monoxide. The enzyme demonstrates a high degree of specificity towards oxidation of lanosterol.64 A wide array of compounds, including azoles, pyridine, pyrimidine and piperazine derivatives, are known inhibitors of C-14 demethylase.65
Examples of single Chinese and botanical medicines derived from TCM
Raymond Cooper, Chun-Tao Che, Daniel Kam-Wah Mok, Charmaine Wing-Yee Tsang in Chinese and Botanical Medicines, 2017
In two separate studies, solvent-extracted garlic and sulfur compounds given to patients with hyperlipidemia lowered cholesterol levels and the researchers suggested that the effects resembled those of HMG-CoA reductase inhibitors. One of the constituents in fresh garlic and in solvent extracts is S-allyl-l-cysteine, which is also present in a large amount in aged garlic extract. This material typically contains 19% of the S-allyl cysteine found in the original cloves. This compound is a potent inhibitor of hepatic cholesterol synthesis. Recent research suggests that the site of inhibition is downstream of lanosterol synthesis, as HMG CoA reductase does not appear to be affected. The accumulation of methyl sterols was detected using gas chromatography in cultured hepatoma cells treated with fresh garlic macerates, suggesting that 4a-methyl oxidase is the principal enzyme inhibited in cholesterol synthesis. It has been concluded that all garlic compounds sharing an allyl-disulfide or allyl sulfhydryl group appear to be inhibitors of the enzyme.
Ketoconazole
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
At low concentrations, ketoconazole, similar to the other azole antifungal agents, has a fungistatic effect on susceptible fungi by inhibiting sterol synthesis in the cell membrane. It inhibits the 14 alpha-demethylation of lanosterol, resulting in reduction in ergosterol synthesis. It differs from its antifungal analogs in that at higher concentrations it is not usually fungicidal to susceptible fungi. Ketoconazole can exert a fungicidal effect at very high concentrations, but such high levels are usually unattainable in tissues after oral dosing (Borgers et al., 1983).
Anti-cataract therapies: is there a need for a new approach based on targeting of aquaporins?
Published in Expert Opinion on Therapeutic Targets, 2021
Vitamin D deficiency has been identified as a risk factor for posterior subcapsular cataract prompting the suggestion that this may be a potential remedy for cataract. Indeed, increasing vitamin D levels in early stages of posterior subcapsular cataract were found to lead to a clearance of the opacification [6]. Promising findings, using lanosterol in animal lenses, were reported, showing restoration of transparency [7,8]. The mechanism of action of lanosterol (25-hydroxycholesterol) was thought to increase chaperone activity leading to dissolution of crystallin aggregates. However, this has not been reproduced in in vitro human lenses [9]. Recent research on cerium oxide has shown multiple actions of ceria nanoparticles on cytoplasmic proteins in lens epithelial cells including as antioxidants, anti-glycating agents, and catalase mimetics, indicating potential for treating different types of cataract [10].
Solubilization and determination of solution thermodynamic properties of itraconazole in different solvents at different temperatures
Published in Drug Development and Industrial Pharmacy, 2019
Sachin K. Jagdale, Rajesh B. Nawale
ITRA is a triazole derivative [1] possessing a wide spectrum of activity against variety of fungal species such as Trichophyton, Candida, Cryptococcus, Neoformans, Aspergillus, Pseudallescheria boydii, Blastomyces [2–4]. It is effective against local fungal infections caused by dermatophytes as well as systemic fungal infections [5,6]. Antifungal activity is mainly linked with cytochrome P450 enzyme – lanosterol C14α demethylase (CYP51). This enzyme catalyzes the major step involved in the conversion of lanosterol to ergosterol [7,8]. ITRA inhibits this CYP51 resulting in accumulation of 14α - methyl sterols in the fungal cell membranes. These sterols are unlike in shape as compared to ergosterol. Amassing of such sterols lead to altered membrane permeability and dysfunctioning of membrane proteins finally leading to fungal cell death [9].
Evaluating posaconazole, its pharmacology, efficacy and safety for the prophylaxis and treatment of fungal infections
Published in Expert Opinion on Pharmacotherapy, 2022
Paraskevi Panagopoulou, Emmanuel Roilides
Ergosterol is an essential component of the fungal cell membrane, like cholesterol in human cells. It is synthesized from lanosterol by the action of lanosterol 14-α-demethylase (also known as CYP51A), a cytochrome P450 (CYP450)-dependent enzyme [13]. Posaconazole docks into the CYP51A and strongly inhibits it, by binding near the heme cofactor with the classic triazole and difluoro phenyl rings. In addition, it has a long side chain that stabilizes the bond especially in the presence of CYP51A mutations. This way it prevents demethylation at positions C-14 and/or C-4 of ergosterol precursors blocking its production [14–16]. This has two significant results: disruption of the functional integrity and increased permeability of the fungal cell membrane, and accumulation of methylated, toxic intermediaries and ergosterol precursors within the cells, leading to cell lysis [17]. In comparison to other azoles, posaconazole exhibits stronger inhibition of lanosterol 14-α-demethylase.
Related Knowledge Centers
- Demethylation
- Steroid
- Triterpene
- Cytochrome P450
- Tetracyclic
- Cycloartenol
- Cholesterol
- Sterol 14-Demethylase