Supergenomic network compression and the discovery of exp1 as a glutathione transferase inhibited by artesunate

Andreas Martin Lisewski, Joel P. Quiros, Caroline L. Ng, Anbu Karani Adikesavan, Kazutoyo Miura, Nagireddy Putluri, Richard T. Eastman, Daniel Scanfeld, Sam J. Regenbogen, Lindsey Altenhofen, Manuel Llinás, Arun Sreekumar, Carole Long, David A. Fidock, Olivier Lichtarge

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

A central problem in biology is to identify gene function. One approach is to infer function in large supergenomic networks of interactions and ancestral relationships among genes; however, their analysis can be computationally prohibitive. We show here that these biological networks are compressible. They can be shrunk dramatically by eliminating redundant evolutionary relationships, and this process is efficient because in these networks the number of compressible elements rises linearly rather than exponentially as in other complex networks. Compression enables global network analysis to computationally harness hundreds of interconnected genomes and to produce functional predictions. As a demonstration, we show that the essential, but functionally uncharacterized Plasmodium falciparum antigen EXP1 is a membrane glutathione S-transferase. EXP1 efficiently degrades cytotoxic hematin, is potently inhibited by artesunate, and is associated with artesunate metabolism and susceptibility in drug-pressured malaria parasites. These data implicate EXP1 in the mode of action of a frontline antimalarial drug.

Original languageEnglish (US)
Pages (from-to)916-928
Number of pages13
JournalCell
Volume158
Issue number4
DOIs
StatePublished - Aug 14 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Lisewski, A. M., Quiros, J. P., Ng, C. L., Adikesavan, A. K., Miura, K., Putluri, N., Eastman, R. T., Scanfeld, D., Regenbogen, S. J., Altenhofen, L., Llinás, M., Sreekumar, A., Long, C., Fidock, D. A., & Lichtarge, O. (2014). Supergenomic network compression and the discovery of exp1 as a glutathione transferase inhibited by artesunate. Cell, 158(4), 916-928. https://doi.org/10.1016/j.cell.2014.07.011