Genome profiling of sterol synthesis shows convergent evolution in parasites and guides chemotherapeutic attack
| Autor: | Torsten Ochsenreiter, Markus R. Wenk, Pascal Mäser, Kapila Gunasekera, Xue Li Guan, Matthias A. Fügi |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Trypanosoma
sterol metabolism sterol biosynthesis inhibitor In silico comparative genomics QD415-436 Computational biology Trypanosoma brucei Biochemistry Cell Line Evolution Molecular chemistry.chemical_compound Endocrinology Ergosterol parasitic diseases polycyclic compounds Animals Cluster Analysis Computer Simulation Parasites hidden Markov model Research Articles Comparative genomics biology Antiparasitic Agents Cell Biology Genomics biology.organism_classification Antiparasitic agent Sterol Markov Chains 3. Good health Sterols chemistry Proteome lipids (amino acids peptides and proteins) hierarchical clustering |
| Zdroj: | Journal of Lipid Research, Vol 55, Iss 5, Pp 929-938 (2014) Journal of lipid research |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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