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J Lipid Res. 2014 May;55(5):929-38. doi: 10.1194/jlr.M048017. Epub 2014 Mar 13.

Genome profiling of sterol synthesis shows convergent evolution in parasites and guides chemotherapeutic attack.

Author information

1
Swiss Tropical and Public Health Institute, Basel, Switzerland.

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.

KEYWORDS:

Giardia; Trypanosoma; comparative genomics; hidden Markov model; hierarchical clustering; sterol biosynthesis inhibitor; sterol metabolism

PMID:
24627128
PMCID:
PMC3995470
DOI:
10.1194/jlr.M048017
[Indexed for MEDLINE]
Free PMC Article

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