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Antifungal drug resistance: Significance and mechanisms
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
Sharvari Dharmaiah, Rania A. Sherif, Pranab K. Mukherjee
Azole resistance has also been associated with alteration in activity of cytochrome P450-dependent 14α-demethylase and that of other ergosterol biosynthesis enzymes, like ∆5-6 desaturase [128–131]. In this regard, Vanden Bossche et al. [132] demonstrated increased microsomal cytochrome P-450 content and subcellular ergosterol synthesis from mevalonate or lanosterol in azole-resistant C. glabrata, indicating that the level of P450-dependent 14α-demethylation of lanosterol was higher in these cells, and contributed to resistance. Azole resistance in C. krusei has been linked to reduced susceptibility of 14α-demethylase because of reduced binding affinity [133]. Over-expression of CYP51A1 in C. albicans and C. glabrata may also account for a decreased susceptibility to azole antifungal agents [134].
Antifungals
Published in Sarah H. Wakelin, Howard I. Maibach, Clive B. Archer, Handbook of Systemic Drug Treatment in Dermatology, 2015
Marie-Louise Daly, Victoria J. Hogarth, Hui Min Liew, Mary Sommerlad, Rachael Morris-Jones
Azole antifungals are a synthetic group of fungistatic agents with a broad spectrum of activity. They are based on a 5-member ring structure and classified into two groups: imidazoles and triazoles. They bind to the iron atom in the haem component of lanosterol-14 demethylase (or CYP51A1, P45014DM) a cytochrome P450 enzyme that converts lanosterol to ergosterol, a major fungal wall component. This leads to arrested fungal growth. Triazoles have a higher specificity of binding than imidazoles, leading to increased potency. Over-expression of CYP51A1 or impairment of energy dependent facilitated diffusion of azoles into fungal cells are mechanisms underlying drug resistance.
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Distribution of CYP51A1 is very widespread among living organisms. Genes encoding CYP51A1 (also called lanosterol 14α-demethylase/sterol 14α-demethylase) are found in yeast, plants, fungi, animals, and even prokaryotes, suggesting that this is among the oldest of the CYP genes. CYP51A1 is a common target of antifungal drugs (e.g., miconazole and ketoconazole), which inhibit CYP51A1 activity and formation of ergosterol. This gene has seven exons and maps to chromosome 7q21.2. It encodes a 503–amino acid protein that has a molecular weight of 56.8 kDa. CYP51A1 catalyzes the 14α-demethylation of lanosterol, an important intermediate in cholesterol synthesis. This demethylation step is the initial checkpoint in the transformation of lanosterol to other sterols. CYP51A1 is the most evolutionarily conserved member of the CYP superfamily (Lepesheva and Waterman 2011); it is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, Saccharomyces cerevisiae, Kluyveromyces lactis, Eremothecium gossypii, Schizosaccharomyces pombe, M. oryzae, A. thaliana, rice, and frog. CYP51A1 catalyzes a complex 14α-demethylation reaction with the aid of cytochrome P450 reductase. In humans, CYP51A1 converts lanosterol to 4,4-dimethyl-5α-cholesta-8,14,24-triene-3β-ol and 24,25-dihydrolanosterol to dihydro-4,4-dimethyl-5α-cholesta-8,14,24-triene-3β-ol. cholesta-8,14,24-triene-3β-ol. The enzyme mRNA expression levels are highest in testis (both round and elongated spermatids), ovary, adrenal, prostate, live, kidney, and lung (Rozman et al. 1996). CYP51A1 in mammals is also responsible for production of the follicular fluid meiosis-activating sterol. Together with the testis meiosis-activating sterol, the product of the downstream sterol Δ14-reductase reaction, these sterols are present at elevated levels in gonads and are involved in oocyte maturation and spermatogenesis (Keber et al. 2013). The Cyp51 knockout mice show embryonic lethality at day 15 postcoitum with features similar to Antley–Bixler syndrome (Keber et al. 2011). Among mammalian P450s, human CYP51 is structurally similar to cholesterol 24-hydroxylase CYP46A1 with 20% sequence identity and CYP3A4 with 21% sequence identity.
Can trophectoderm RNA analysis predict human blastocyst competency?
Published in Systems Biology in Reproductive Medicine, 2019
Panagiotis Ntostis, Georgia Kokkali, David Iles, John Huntriss, Maria Tzetis, Helen Picton, Konstantinos Pantos, David Miller
Several gene families with similar functions were shared with the Kirkegaard (*) study (Kirkegaard et al. 2015), including ATP binding cassette subfamilies (ABCG2, ABCB10*), cytochrome 450 family members, including CYP11A1, CYP51A1, CYP2F1*, and the hydroxysteroid dehydrogenases HSD17B1 and HSD17B11*. A full list of shared gene families is available in Supplemental Table 4. Differences between their study and ours may have been due to a combination of factors, including the use of library construction not well suited to ultra-low initial RNA inputs. The absence of a de novo assembly step of the RNA sequencing data may also have impeded the detection of de novo assembled transcripts. Due to the relatively high variation reported for TE gene expression, the Kirkegaard study may also have lacked power to detect differentially expressed transcripts. We tried to avoid these pitfalls by applying a more evenly distributed, ultra-sensitive deep RNA sequencing approach and used more samples (8 in total) and only reported transcripts with differential fold-change above or close to 3.
Regulation of cytochrome P450 enzyme activity and expression by nitric oxide in the context of inflammatory disease
Published in Drug Metabolism Reviews, 2020
Edward T. Morgan, Cene Skubic, Choon-myung Lee, Kaja Blagotinšek Cokan, Damjana Rozman
To study the mechanisms of P450 down-regulation by NO, we established human Huh7 hepatoma and HeLa cell lines expressing CYP2B6 via lentiviral transduction. These cells recapitulated the down-regulation of CYP2B6 protein by NO donors (100–500 μM) observed in primary human hepatocytes, in the absence of any effect on CYP2B6 mRNA (Lee et al. 2017). CYP2B6 with a C-terminal V5 peptide tag (CYP2B6V5) showed the same regulation. This occurred in the presence of cycloheximide, demonstrating that it is due to stimulated protein degradation (Lee et al. 2017). Since neither Huh7 nor HeLa cells mount a robust induction of NOS2 in response to inflammatory mediators, we also co-expressed CYP2B6V5 in HeLa cells with a tetracycline-regulated human NOS2 gene, and demonstrated that NO derived from NOS2 down-regulated the 2B6V5 protein (Lee et al. 2017). Using the same approaches, we demonstrated that native and V5-tagged human CYP51A1 (Park et al. 2017), CYP2J2V5 (Park et al. 2018) and CYP2A6V5 (Cerrone Jr et al. 2020) are each susceptible to NO-mediated degradation. CYP51A1 is a ubiquitous enzyme that catalyzes lanosterol 14α-demethylation, an obligatory step in the biosynthesis of cholesterol and intermediate bioactive sterols (Stromstedt et al. 1996; Rozman et al. 2002). Despite being expressed in all cells it shows tissue-dependent regulation, including responses to cAMP signaling in spermatogenesis (Rozman et al. 1999) and in the liver (Halder et al. 2002). CYP2J2 is an arachidonic acid epoxygenase with important roles in inflammation and the cardiovascular system (Karkhanis et al. 2017). It will be important to discover whether their regulation by NO in disease states contributes to disease pathology or mitigation. On the other hand, CYP3A4V5 and CYP3A5V5 were refractory to down-regulation by NO (Lee et al. 2017).