Interaction of azole antifungal agents with cytochrome P-45014DM purified from Saccharomyces cerevisiae microsomes

Yoshida, Yasuhiko; Aoyama, Yuri

doi:10.1016/0006-2952(87)90694-0

Cited by 226 publications

(31 citation statements)

References 17 publications

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“…Δ PdsreA , Δ PdsreB and ΔΔ PdsreAB also increased sensitivity to terbinafine fungicide (Fig 2B), an Erg1 inhibitor [37]. However, strains only defective for PdsreA but not PdsreB were hypersensitive to tridemorph (Fig 2B), an Erg2 inhibitor [8]. The defect of fungicide resistance in gene deletion mutants was restored by introduction and re-expression of a functional copy of PdsreA or PdsreB into its respective mutant (Fig 2A and 2B).…”

Section: Resultsmentioning

confidence: 99%

“…DMI fungicides inhibit the activity of the cytochrome P450-dependent sterol 14α-demethylase (Cyp51) and thus, block C14-demethylation of lanosterol in fungal pathogens [8,9]. DMI resistance has been reported in many phytopathogenic fungi, and major mechanisms leading to resistance include point mutations or overexpression of CYP51 genes and overexpression of several transporter protein-coding genes [10,11,12,13,14,15,16,17,18].…”

Section: Introductionmentioning

confidence: 99%

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Functional analysis of two sterol regulatory element binding proteins in Penicillium digitatum

et al. 2017

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The sterol regulatory element binding proteins (SREBPs) are key regulators for sterol homeostasis in most fungi. In the citrus postharvest pathogen Penicillium digitatum, the SREBP homolog is required for fungicide resistance and regulation of CYP51 expression. In this study, we identified another SREBP transcription factor PdSreB in P. digitatum, and the biological functions of both SREBPs were characterized and compared. Inactivation of PdsreA, PdsreB or both genes in P. digitatum reduced ergosterol contents and increased sensitivities to sterol 14-α-demethylation inhibitors (DMIs) and cobalt chloride. Fungal strains impaired at PdsreA but not PdsreB increased sensitivity to tridemorph and an iron chelator 2,2’-dipyridyl. Virulence assays on citrus fruit revealed that fungal strains impaired at PdsreA, PdsreB or both induce maceration lesions similar to those induced by wild-type. However, ΔPdsreA, ΔPdsreB or the double mutant strain rarely produce aerial mycelia on infected citrus fruit peels. RNA-Seq analysis showed the broad regulatory functions of both SREBPs in biosynthesis, transmembrane transportation and stress responses. Our results provide new insights into the conserved and differentiated regulatory functions of SREBP homologs in plant pathogenic fungi.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional analysis of two sterol regulatory element binding proteins in Penicillium digitatum

et al. 2017

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“…3C). Azole drugs inhibit Erg11, which is a cytochrome P450 enzyme having heme as a cofactor [27,28]. Heme is primarily synthesized in the mitochondria and previous studies revealed that mitochondrial mutants of Candida species have reduced ergosterol levels [29,30].…”

Section: Resultsmentioning

confidence: 99%

The lysine biosynthetic enzyme Lys4 influences iron metabolism, mitochondrial function and virulence in Cryptococcus neoformans

Park

et al. 2016

Biochemical and Biophysical Research Communications

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The lysine biosynthesis pathway via α-aminoadipate in fungi is considered an attractive target for antifungal drugs due to its absence in mammalian hosts. The iron-sulfur cluster-containing enzyme homoaconitase converts homocitrate to homoisocitrate in the lysine biosynthetic pathway, and is encoded by LYS4 in the model yeast Saccharomyces cerevisiae. In this study, we identified the ortholog of LYS4 in the human fungal pathogen, Cryptococcus neoformans, and found that LYS4 expression is regulated by iron levels and by the iron-related transcription factors Hap3 and HapX. Deletion of the LYS4 gene resulted in lysine auxotrophy suggesting that Lys4 is essential for lysine biosynthesis. Our study also revealed that lysine uptake was mediated by two amino acid permeases, Aap2 and Aap3, and influenced by nitrogen catabolite repression (NCR). Furthermore, the lys4 mutant showed increased sensitivity to oxidative stress, agents that challenge cell wall/membrane integrity, and azole antifungal drugs. We showed that these phenotypes were due in part to impaired mitochondrial function as a result of LYS4 deletion, which we propose disrupts iron homeostasis in the organelle. The combination of defects are consistent with our observation that the lys4 mutant was attenuated virulence in a mouse inhalation model of cryptococcosis.

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“…These findings suggest that enzyme activities were decreased significantly, probably due to the low ROS levels, low lipid peroxidation, the potent antioxidant effect of clotrimazole, and the protective effect of clotrimazole is cytochrome P 450 -dependent. Clotrimazole inhibits their effects on cellular metabolism and signaling, especially in calcium-dependent processes, thus causing both reduced calcium overload and reduced probability of mitochondrial potential collapse [18,19]. In addition, since the P 450 system is very sensitive to oxygen, clotrimazole may play an important role in the regulation of Ca 2+ handling under normal or ischemic conditions by reducing receptor-operated Ca 2+ influx in human neutrophils and platelets [7,20].…”

Section: Discussionmentioning

confidence: 99%

Ovarian-Protective Effects of Clotrimazole on Ovarian Ischemia/Reperfusion Injury in a Rat Ovarian-Torsion Model

Osmanağaoğlu¹,

Kesim²,

Yuluğ³

et al. 2012

Gynecol Obstet Invest

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Background/Aims: To evaluate the ovarian-protective effects of clotrimazole on ovarian ischemia/reperfusion injury in a rat ovarian-torsion model. Methods: 32 Sprague-Dawleyrats were randomly divided into four groups: (1) ischemia group (n = 8) in which only left adnexal torsion was performed for 2 h, but no treatment was given; (2) vehicle group (n = 8) in which left adnexal torsion was performed for 2 h and at the end of 2 h ischemia polyethylene glycol (3% PEG, 1 ml, i.p.) was administered and a 24-hour reperfusion was continued; (3) clotrimazole group (n = 8) in which left adnexal torsion was performed for 2 h and at the end of 2 h ischemia clotrimazole (30 mg/kg, i.p.) was administered and a 24-hour reperfusion was continued, and (4) control group (sham-operated, n = 6) in which no adnexal torsion and no treatment were given. The criteria for ovarian ischemia were follicular cell degeneration, vascular congestion, hemorrhage and infiltration by inflammatory cells. Each specimen was scored for each criterion (0, none; 1, mild; 2, moderate; 3, severe). Results: Clotrimazole significantly decreased plasma levels of serum malondialdehyde, ischemia-modified albumin, and total oxidant status. Conclusion: This study showed the ovarian-protective effects of clotrimazole on ovarian ischemia/reperfusion injury.

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Interaction of azole antifungal agents with cytochrome P-45014DM purified from Saccharomyces cerevisiae microsomes

Cited by 226 publications

References 17 publications

Functional analysis of two sterol regulatory element binding proteins in Penicillium digitatum

Functional analysis of two sterol regulatory element binding proteins in Penicillium digitatum

The lysine biosynthetic enzyme Lys4 influences iron metabolism, mitochondrial function and virulence in Cryptococcus neoformans

Ovarian-Protective Effects of Clotrimazole on Ovarian Ischemia/Reperfusion Injury in a Rat Ovarian-Torsion Model

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