当前位置：
X-MOL 学术
›
Metallomics
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
The cytochrome b5 CybE is regulated by iron availability and is crucial for azole resistance in A. fumigatus
Metallomics ( IF 2.9 ) Pub Date : 2017-10-26 00:00:00 , DOI: 10.1039/c7mt00110j Matthias Misslinger 1, 2, 3, 4, 5 , Fabio Gsaller 6, 7, 8, 9, 10 , Peter Hortschansky 11, 12, 13, 14 , Christoph Müller 14, 15, 16, 17, 18 , Franz Bracher 14, 15, 16, 17, 18 , Michael J. Bromley 6, 7, 8, 9, 10 , Hubertus Haas 1, 2, 3, 4, 5
Metallomics ( IF 2.9 ) Pub Date : 2017-10-26 00:00:00 , DOI: 10.1039/c7mt00110j Matthias Misslinger 1, 2, 3, 4, 5 , Fabio Gsaller 6, 7, 8, 9, 10 , Peter Hortschansky 11, 12, 13, 14 , Christoph Müller 14, 15, 16, 17, 18 , Franz Bracher 14, 15, 16, 17, 18 , Michael J. Bromley 6, 7, 8, 9, 10 , Hubertus Haas 1, 2, 3, 4, 5
Affiliation
|
Cytochrome P450 enzymes (P450) play essential roles in redox metabolism in all domains of life including detoxification reactions and sterol biosynthesis. The activity of P450s is fuelled by two electron-transferring mechanisms, heme-independent P450 reductase (CPR) and the heme-dependent cytochrome b5 (CYB5)/cytochrome b5 reductase (CB5R) system. In this study, we characterised the role and regulation of the cytochrome b5 CybE in the fungal pathogen Aspergillus fumigatus. Deletion of the CybE encoding gene (cybE) caused a severe growth defect in two different A. fumigatus isolates, emphasising the importance of the CB5R system in this pathogen, while the non-essentiality of cybE indicates the partial redundancy of the CPR and CB5R systems. Interestingly, the growth defect caused by the cybE loss of function was even more drastic in A. fumigatus strain AfS77 compared to strain A1160P+ indicating a strain-dependent degree of compensation, which is supported by azole resistance studies. In agreement with CybE being important for the assistance of the ergosterol biosynthetic P450 Cyp51, deletion of cybE decreased resistance to the Cyp51-targeting antifungal voriconazole and caused accumulation of the ergosterol pathway intermediate eburicol. Northern analysis indicated that CybE deficiency leads to the compensatory transcriptional upregulation of Cyp51-encoding cyp51A and CPR-encoding cprA. Overexpression of cybE did not affect azole resistance suggesting that CybE activity is not rate limiting. Expression of cybE was found to be repressed during iron starvation by the iron-regulatory transcription factor HapX demonstrating iron dependence of CybE not only at the level of enzyme activity but also at the level of gene expression.
中文翻译：
细胞色素b 5 CybE受铁的可利用性调节，对于烟曲霉的唑耐药性至关重要
细胞色素P450酶（P450）在生活的所有领域（包括排毒反应和固醇生物合成）中的氧化还原代谢中都起着重要作用。P450的活性由两种电子转移机制提供动力，即不依赖血红素的P450还原酶（CPR）和不依赖血红素的细胞色素b 5（CYB5）/细胞色素b 5还原酶（CB5R）系统。在这项研究中，我们表征了真菌病原体烟曲霉中细胞色素b 5 CybE的作用和调控。CybE编码基因（cybE）的缺失在两种不同的烟曲霉中引起严重的生长缺陷。分离，强调CB5R系统在这种病原体中的重要性，而cybE的非必需性则表明CPR和CB5R系统的部分冗余。有趣的是，在烟曲霉菌株AfS77中，由cybE功能丧失引起的生长缺陷甚至比菌株A1160P +更为严重，表明菌株依赖性的补偿程度，这得到了唑抗性研究的支持。同意CybE对麦角固醇生物合成P450 Cyp51的协助至关重要，删除cybE降低了针对Cyp51的抗真菌伏立康唑的耐药性，并导致了麦角固醇途径中间体eburicol的积累。Northern分析表明，CYBE缺乏导致补偿性的CYP51编码转录上调cyp51A和编码CPR- CPRA。cybE的过表达并不影响对唑的抗性，这表明CybE的活性不受速率的限制。发现铁饥饿期间，铁调节转录因子HapX抑制了cybE的表达，这表明CybE的铁依赖性不仅在酶活性水平上，而且在基因表达水平上。
更新日期：2017-11-16
中文翻译：
细胞色素b 5 CybE受铁的可利用性调节，对于烟曲霉的唑耐药性至关重要
细胞色素P450酶（P450）在生活的所有领域（包括排毒反应和固醇生物合成）中的氧化还原代谢中都起着重要作用。P450的活性由两种电子转移机制提供动力，即不依赖血红素的P450还原酶（CPR）和不依赖血红素的细胞色素b 5（CYB5）/细胞色素b 5还原酶（CB5R）系统。在这项研究中，我们表征了真菌病原体烟曲霉中细胞色素b 5 CybE的作用和调控。CybE编码基因（cybE）的缺失在两种不同的烟曲霉中引起严重的生长缺陷。分离，强调CB5R系统在这种病原体中的重要性，而cybE的非必需性则表明CPR和CB5R系统的部分冗余。有趣的是，在烟曲霉菌株AfS77中，由cybE功能丧失引起的生长缺陷甚至比菌株A1160P +更为严重，表明菌株依赖性的补偿程度，这得到了唑抗性研究的支持。同意CybE对麦角固醇生物合成P450 Cyp51的协助至关重要，删除cybE降低了针对Cyp51的抗真菌伏立康唑的耐药性，并导致了麦角固醇途径中间体eburicol的积累。Northern分析表明，CYBE缺乏导致补偿性的CYP51编码转录上调cyp51A和编码CPR- CPRA。cybE的过表达并不影响对唑的抗性，这表明CybE的活性不受速率的限制。发现铁饥饿期间，铁调节转录因子HapX抑制了cybE的表达，这表明CybE的铁依赖性不仅在酶活性水平上，而且在基因表达水平上。
京公网安备 11010802027423号