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标题：Genome profiling of sterol synthesis shows convergent evolution in parasites and guides chemotherapeutic attack
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作者：Matthias A. Fügi ; Kapila Gunasekera ; Torsten Ochsenreiter 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2014
卷号：55
期号：5
页码：929-938
DOI：10.1194/jlr.M048017
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：Sterols are an essential class of lipids in eukaryotes, where they serve as structural components of membranes and play important roles as signaling molecules. Sterols are also of high pharmacological significance: cholesterol-lowering drugs are blockbusters in human health, and inhibitors of ergosterol biosynthesis are widely used as antifungals. Inhibitors of ergosterol synthesis are also being developed for Chagas’s disease, caused by Trypanosoma cruzi . Here we develop an in silico pipeline to globally evaluate sterol metabolism and perform comparative genomics. We generate a library of hidden Markov model-based profiles for 42 sterol biosynthetic enzymes, which allows expressing the genomic makeup of a given species as a numerical vector. Hierarchical clustering of these vectors functionally groups eukaryote proteomes and reveals convergent evolution, in particular metabolic reduction in obligate endoparasites. We experimentally explore sterol metabolism by testing a set of sterol biosynthesis inhibitors against trypanosomatids, Plasmodium falciparum , Giardia , and mammalian cells, and by quantifying the expression levels of sterol biosynthetic genes during the different life stages of T. cruzi and Trypanosoma brucei . The phenotypic data correlate with genomic makeup for simvastatin, which showed activity against trypanosomatids. Other findings, such as the activity of terbinafine against Giardia , are not in agreement with the genotypic profile.
关键词：sterol metabolism ; sterol biosynthesis inhibitor ; comparative genomics ; hidden Markov model ; hierarchical clustering ; Trypanosoma ; Giardia