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Disruption of the Plasmodium falciparum Life Cycle through Transcriptional Reprogramming by Inhibitors of Jumonji Demethylases.

TitleDisruption of the Plasmodium falciparum Life Cycle through Transcriptional Reprogramming by Inhibitors of Jumonji Demethylases.
Publication TypeJournal Article
Year of Publication2020
AuthorsMatthews KA, Senagbe KM, Nötzel C, Gonzales CA, Tong X, Rijo-Ferreira F, Bhanu NV, Miguel-Blanco C, Lafuente-Monasterio MJose, Garcia BA, Kafsack BFC, Martinez ED
JournalACS Infect Dis
Volume6
Issue5
Pagination1058-1075
Date Published2020 05 08
ISSN2373-8227
Abstract

Little is known about the role of the three Jumonji C (JmjC) enzymes in Plasmodium falciparum (Pf). Here, we show that JIB-04 and other established inhibitors of mammalian JmjC histone demethylases kill asexual blood stage parasites and are even more potent at blocking gametocyte development and gamete formation. In late stage parasites, JIB-04 increased levels of trimethylated lysine residues on histones, suggesting the inhibition of P. falciparum Jumonji demethylase activity. These epigenetic defects coincide with deregulation of invasion, cell motor, and sexual development gene programs, including gene targets coregulated by the PfAP2-I transcription factor and chromatin-binding factor, PfBDP1. Mechanistically, we demonstrate that PfJmj3 converts 2-oxoglutarate to succinate in an iron-dependent manner consistent with mammalian Jumonji enzymes, and this catalytic activity is inhibited by JIB-04 and other Jumonji inhibitors. Our pharmacological studies of Jumonji activity in the malaria parasite provide evidence that inhibition of these enzymatic activities is detrimental to the parasite.

DOI10.1021/acsinfecdis.9b00455
Alternate JournalACS Infect Dis
PubMed ID32272012
PubMed Central IDPMC7748244
Grant ListR01 AI141965 / AI / NIAID NIH HHS / United States
R21 AI139408 / AI / NIAID NIH HHS / United States

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