Cytochrome P450 of Fungi: Primary Target for Azole Antifungal Agents

Yoshida, Yasuhiko

doi:10.1007/978-1-4612-3730-3_11

Cited by 117 publications

(70 citation statements)

References 110 publications

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“…Incomplete inhibition of ergosterol biosynthesis was more pronounced with fluconazole because even at 1000 nM, isolates NCPF 3363, J913004\1, 6406\8, C26 and C40 still produced 16-78 % of the amounts found in control conditions. Prevention of CO-complex formation in the reduced microsomal cytochrome P450 preparations is another assay that can be used to test the affinity of the protein for an azole (Vanden Bossche et al, 1987 ;Yoshida, 1988). With this method, a constant content of 0n1 nmol cytochrome P450 ml −" is used, enabling direct comparison of susceptibility between different isolates.…”

Section: Erg11p Activity and Sensitivity Determinationmentioning

confidence: 99%

Contribution of mutations in the cytochrome P450 14α-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans

et al. 1999

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The cytochrome P450 14α-demethylase, encoded by the ERG11 (CYP51) gene, is the primary target for the azole class of antifungals. Changes in the azole affinity of this enzyme caused by amino acid substitutions have been reported as a resistance mechanism. Nine Candida albicans strains were used in this study. The ERG11 base sequence of seven isolates, of which only two were azole-sensitive, were determined. The ERG11 base sequences of the other two strains have been published previously. In these seven isolates, 12 different amino acid substitutions were identified, of which six have not been described previously (A149V, D153E, E165Y, S279F, V452A and G465S). In addition, 16 silent mutations were found. Two different biochemical assays, subcellular sterol biosynthesis and CO binding to reduced microsomal fractions, were used to evaluate the sensitivity of the cytochromes for fluconazole and itraconazole. Enzyme preparations from four isolates showed reduced itraconazole susceptibility, whereas more pronounced resistance to fluconazole was observed in five isolates. A three-dimensional model of C. albicans Cyp51p was used to position all 29 reported substitutions, 98 in total identified in 53 sequences. These 29 substitutions were not randomly distributed over the sequence but clustered in three regions from amino acids 105 to 165, from 266 to 287 and from 405 to 488, suggesting the existence of hotspot regions. Of the mutations found in the two N-terminal regions only Y132H was demonstrated to be of importance for azole resistance. In the Cterminal region three mutations are associated with resistance, suggesting that the non-characterized substitutions found in this region should be prioritized for further analysis.

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Section: Erg11p Activity and Sensitivity Determinationmentioning

confidence: 99%

Contribution of mutations in the cytochrome P450 14α-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans

et al. 1999

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“…According to their chemical structure, Azoles are grouped into either class of imidazoles or triazoles. Penconazole (1-(2-(2,4-dichlorophenyl)-pentyl)-1H-1,2,4-triazole), is asystemic triazole fungicide and it santifungal activity based on inhibition of lanosterol-14α-demethylase(CYP51) (Yoshida, 1988;Podust et al, 2001), which are phylogenetically widely distributed in mycobacteria, fungi, plants, animals and humans and highly conserved cytochrome P450 monooxygenase (McLean et al 2002;Lepesheva et al, 2003). Azole compounds are rather lipophilic and penetrate to the cytochrome P450 enzymes within the endoplasmatic reticulum.…”

Section: Introductionmentioning

confidence: 99%

Potential therapeutic effect of turmeric (Curcuma longa) against adverse effects of penconazole fungicide to white rats

Rasoul

Marei

2016

IJPT

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This study aimed to investigate the prophylactic effect of turmeric (Curcuma longa) Rhizome Ethanolic extract (CLRE) at 250 mg/kg as antioxidant effects against penconazole induced sub-acute toxicity. Hepatic, renal and testicular pathological changes caused by oxidative damage induced by penconazole in rats were biochemically and histologically evaluated. Male rats were treated with penconazole, via oral route, at doses of 0.5 mg/ kg body weight (b.w.; acute reference dose, ARfD), 25 mg/kg b.w. (no observed adverse effects level, NOAEL) and 100 mg/ kg b.w. (1/20 lethal dose [LD 50 ]) for 28 consecutive days. Penconazole treatments had significant (p < 0.05) and gradual reductions in body and relative testicular weight accompanied by significant elevation in the relative liver and kidney weights. Significant increase serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dhydrogenase(LDH), gamma-glutamyl transferase (GGT), creatinine (Cre), uric acid and blood glucose was observed due to penconazole treatments. However, total protein and testosterone hormone were significantly decreased. Exposure to penconazole caused increase in lipid peroxidation (LPO) and decreased of liver and kidney antioxidant enzymes activity as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Histopathological studies confirmed the ameliorative beneficial effects of turmeric biochemical parameters. On the basis of this study, the use of tumeric rhizomes as a functional food or as a nutraceutical product could be a useful approach to protect individuals who are regularly exposed to penconazole.

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“…Additionally, a further enzyme of the sterol biosynthetic pathway requires CPR, namely squalene epoxidase [16]. Yeast gene disruption studies on CPR indicated surprisingly that the protein was dispensible [17,18] and that ergosterol was the predominant sterol with or without CPR being present in strains [17,19].…”

Section: Introductionmentioning

confidence: 99%

Biodiversity of the P450 catalytic cycle: yeast cytochrome b₅/NADH cytochrome b₅ reductase complex efficiently drives the entire sterol 14‐demethylation (CYP51) reaction

et al. 1999

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The widely accepted catalytic cycle of cytochromes P450 (CYP) involves the electron transfer from NADPH cytochrome P450 reductase (CPR), with a potential for second electron donation from the microsomal cytochrome b 5 /NADH cytochrome b 5 reductase system. The latter system only supported CYP reactions inefficiently. Using purified proteins including Candida albicans CYP51 and yeast NADPH cytochrome P450 reductase, cytochrome b 5 and NADH cytochrome b 5 reductase, we show here that fungal CYP51 mediated sterol 14K K-demethylation can be wholly and efficiently supported by the cytochrome b 5 /NADH cytochrome b 5 reductase electron transport system. This alternative catalytic cycle, where both the first and second electrons were donated via the NADH cytochrome b 5 electron transport system, can account for the continued ergosterol production seen in yeast strains containing a disruption of the gene encoding CPR.z 1999 Federation of European Biochemical Societies.

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Cytochrome P450 of Fungi: Primary Target for Azole Antifungal Agents

Cited by 117 publications

References 110 publications

Contribution of mutations in the cytochrome P450 14α-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans

Contribution of mutations in the cytochrome P450 14α-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans

Potential therapeutic effect of turmeric (Curcuma longa) against adverse effects of penconazole fungicide to white rats

Biodiversity of the P450 catalytic cycle: yeast cytochrome b₅/NADH cytochrome b₅ reductase complex efficiently drives the entire sterol 14‐demethylation (CYP51) reaction

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Cytochrome P450 of Fungi: Primary Target for Azole Antifungal Agents

Cited by 117 publications

References 110 publications

Contribution of mutations in the cytochrome P450 14α-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans

Contribution of mutations in the cytochrome P450 14α-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans

Potential therapeutic effect of turmeric (Curcuma longa) against adverse effects of penconazole fungicide to white rats

Biodiversity of the P450 catalytic cycle: yeast cytochrome b5/NADH cytochrome b5 reductase complex efficiently drives the entire sterol 14‐demethylation (CYP51) reaction

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Biodiversity of the P450 catalytic cycle: yeast cytochrome b₅/NADH cytochrome b₅ reductase complex efficiently drives the entire sterol 14‐demethylation (CYP51) reaction