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Genome profiling of sterol synthesis shows convergent evolution in parasites and guides chemotherapeutic attack
- Source :
- Journal of Lipid Research, Vol 55, Iss 5, Pp 929-938 (2014), Journal of lipid research
- Publication Year :
- 2014
- Publisher :
- The American Society for Biochemistry and Molecular Biology, 2014.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Journal of Lipid Research, Vol 55, Iss 5, Pp 929-938 (2014), Journal of lipid research
- Accession number :
- edsair.doi.dedup.....fc5a873ab561d7eaf559317859a488b2