TY - JOUR
T1 - Disruption of the plasmodium falciparum life cycle through transcriptional reprogramming by inhibitors of jumonji demethylases
AU - Matthews, Krista A.
AU - Senagbe, Kossi M.
AU - Nötzel, Christopher
AU - Gonzales, Christopher A.
AU - Tong, Xinran
AU - Rijo-Ferreira, Filipa
AU - Bhanu, Natarajan V.
AU - Miguel-Blanco, Celia
AU - Lafuente-Monasterio, Maria Jose
AU - Garcia, Benjamin A.
AU - Kafsack, Björn F.C.
AU - Martinez, Elisabeth D.
N1 - Publisher Copyright:
© 2020 American Chemical Society
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Demethylases
KW - Gametocytes
KW - JIB-04
KW - Jumonji inhibitors
KW - Malaria
KW - Plasmodium falciparum
KW - Transcriptional reprogramming
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U2 - 10.1021/acsinfecdis.9b00455
DO - 10.1021/acsinfecdis.9b00455
M3 - Article
C2 - 32272012
AN - SCOPUS:85084721111
SN - 2373-8227
VL - 6
SP - 1058
EP - 1075
JO - ACS infectious diseases
JF - ACS infectious diseases
IS - 5
ER -