Cytochrome P450 monooxygenase CYP53 family in fungi: comparative structural and evolutionary analysis and its role as a common alternative anti-fungal drug target.
Cytochrome P450 monooxygenase CYP53 family in fungi: comparative structural and evolutionary analysis and its role as a common alternative anti-fungal drug target.
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DOI：
10.1371/journal.pone.0107209
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Syed K
中科院分区：
文献类型：
--
作者：
Jawallapersand P;Mashele SS;Kovačič L;Stojan J;Komel R;Pakala SB;Kraševec N;Syed K
细胞色素P450单加氧酶（CYPs/P450）是一种血红素硫酸酯蛋白，由于其立体和区域特异性氧化活性，其作为抗病原微生物的药物靶点的作用已被探索。我们旨在评估CYP53家族作为动物（包括人类）和植物病原真菌的常见替代药物靶点的作用及其在真菌介导的木材降解中的作用。对真菌物种的全基因组分析显示，在子囊菌和担子菌中存在CYP53成员。担子菌基因组中CYP53成员的数量高于子囊菌。在子囊菌中仅发现2个CYP53亚家族，在担子菌中发现6个亚家族，提示子囊菌在门分化过程中丢失了CYP53 p450。根据系统发育和基因结构分析，担子菌中CYP53 p450的富集是由于其基因组中CYP53 p450的大量重复。在子囊菌CYP53 p450中发现了许多氨基酸（103个）的保守性，而担子菌CYP53 p450中只有7个。3d建模和活性位点空腔定位数据显示，子囊菌CYP53 p450具有高度保守的蛋白质结构，其中活性位点空腔中78%的氨基酸被发现是保守的。由于子囊菌CYP53 P450活性位点空腔的这种刚性性质，任何针对P450家族的抑制剂都可以作为常见的抗真菌药物靶点，特别是针对致病性子囊菌。担子菌CYP53 p450在基因和蛋白水平上的动态特性表明，这些p450注定要获得新的功能。CYP53 p450的功能分析有力地支持了我们的假设，即子囊菌CYP53 p450对有毒分子的解毒能力有限，而担子菌CYP53 p450则发挥了额外的作用，即参与木材及其衍生成分的降解。本研究首次报道了真菌P450家族的全基因组比较结构（基因和蛋白质结构水平）和进化分析。
Cytochrome P450 monooxygenases (CYPs/P450s) are heme-thiolate proteins whose role as a drug target against pathogenic microbes has been explored because of their stereo- and regio-specific oxidation activity. We aimed to assess the CYP53 family's role as a common alternative drug target against animal (including human) and plant pathogenic fungi and its role in fungal-mediated wood degradation. Genome-wide analysis of fungal species revealed the presence of CYP53 members in ascomycetes and basidiomycetes. Basidiomycetes had a higher number of CYP53 members in their genomes than ascomycetes. Only two CYP53 subfamilies were found in ascomycetes and six subfamilies in basidiomycetes, suggesting that during the divergence of phyla ascomycetes lost CYP53 P450s. According to phylogenetic and gene-structure analysis, enrichment of CYP53 P450s in basidiomycetes occurred due to the extensive duplication of CYP53 P450s in their genomes. Numerous amino acids (103) were found to be conserved in the ascomycetes CYP53 P450s, against only seven in basidiomycetes CYP53 P450s. 3D-modelling and active-site cavity mapping data revealed that the ascomycetes CYP53 P450s have a highly conserved protein structure whereby 78% amino acids in the active-site cavity were found to be conserved. Because of this rigid nature of ascomycetes CYP53 P450s' active site cavity, any inhibitor directed against this P450 family can serve as a common anti-fungal drug target, particularly toward pathogenic ascomycetes. The dynamic nature of basidiomycetes CYP53 P450s at a gene and protein level indicates that these P450s are destined to acquire novel functions. Functional analysis of CYP53 P450s strongly supported our hypothesis that the ascomycetes CYP53 P450s ability is limited for detoxification of toxic molecules, whereas basidiomycetes CYP53 P450s play an additional role, i.e. involvement in degradation of wood and its derived components. This study is the first report on genome-wide comparative structural (gene and protein structure-level) and evolutionary analysis of a fungal P450 family.
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DOI：
10.1007/s004380050552
发表时间：
1997-09-01
期刊：
MOLECULAR AND GENERAL GENETICS
影响因子：
--
作者：
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影响因子：
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发表时间：
2011-02-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
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作者：
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影响因子：
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