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Analysis of the Protein Domain and Domain Architecture Content in Fungi and Its Application in the Search of New Antifungal Targets

机译：真菌中蛋白质结构域和结构域含量的分析及其在寻找新的抗真菌靶标中的应用

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Over the past several years fungal infections have shown an increasing incidence in the susceptible population, and caused high mortality rates. In parallel, multi-resistant fungi are emerging in human infections. Therefore, the identification of new potential antifungal targets is a priority. The first task of this study was to analyse the protein domain and domain architecture content of the 137 fungal proteomes (corresponding to 111 species) available in UniProtKB (UniProt KnowledgeBase) by January 2013. The resulting list of core and exclusive domain and domain architectures is provided in this paper. It delineates the different levels of fungal taxonomic classification: phylum, subphylum, order, genus and species. The analysis highlighted Aspergillus as the most diverse genus in terms of exclusive domain content. In addition, we also investigated which domains could be considered promiscuous in the different organisms. As an application of this analysis, we explored three different ways to detect potential targets for antifungal drugs. First, we compared the domain and domain architecture content of the human and fungal proteomes, and identified those domains and domain architectures only present in fungi. Secondly, we looked for information regarding fungal pathways in public repositories, where proteins containing promiscuous domains could be involved. Three pathways were identified as a result: lovastatin biosynthesis, xylan degradation and biosynthesis of siroheme. Finally, we classified a subset of the studied fungi in five groups depending on their occurrence in clinical samples. We then looked for exclusive domains in the groups that were more relevant clinically and determined which of them had the potential to bind small molecules. Overall, this study provides a comprehensive analysis of the available fungal proteomes and shows three approaches that can be used as a first step in the detection of new antifungal targets.
机译：在过去的几年中，真菌感染在易感人群中显示出越来越高的发病率，并导致很高的死亡率。同时，在人类感染中出现了多抗性真菌。因此，确定新的潜在抗真菌目标是当务之急。这项研究的首要任务是分析2013年1月UniProtKB（UniProt KnowledgeBase）中提供的137种真菌蛋白质组（对应111种）的蛋白质结构域和结构域结构内容。核心和专有结构域和结构域结构的最终清单为本文提供。它描述了真菌分类学分类的不同级别：门，门下，有序，属和种。该分析突出显示曲霉属是排他性领域内容中最多样化的属。此外，我们还研究了在不同生物中哪些域可能被认为是混杂的。作为该分析的应用，我们探索了三种不同的方法来检测抗真菌药物的潜在靶标。首先，我们比较了人类和真菌蛋白质组的域和域架构内容，并确定了仅存在于真菌中的那些域和域架构。其次，我们在公共存储库中寻找有关真菌途径的信息，其中可能包含含有混杂域的蛋白质。结果确定了三个途径：洛伐他汀的生物合成，木聚糖的降解和西罗血红素的生物合成。最后，我们将研究真菌的子集分为五类，具体取决于它们在临床样品中的出现。然后，我们在与临床更相关的组中寻找排他性结构域，并确定其中哪些具有结合小分子的潜力。总的来说，这项研究对可用的真菌蛋白质组进行了全面的分析，并显示了三种可以用作检测新抗真菌靶标的第一步的方法。

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