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

Autor: Matthews KA; Department of Pharmacology, The University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, Texas 75390, United States., Senagbe KM; Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, Texas 75390, United States., Nötzel C; Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Avenue, W-705, New York, New York 10065, United States.; Biochemistry, Cell & Molecular Biology Graduate Program, Weill Cornell Medicine, 1300 York Avenue, W-705, New York, New York 10065, United States., Gonzales CA; Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, Texas 75390, United States., Tong X; Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Avenue, W-705, New York, New York 10065, United States., Rijo-Ferreira F; Department of Neuroscience, The University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, Texas 75390, United States., Bhanu NV; Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd., Bldg. 421, Philadelphia, Pennsylvania 19104, United States., Miguel-Blanco C; Tres Cantos Medicines Development Campus, GlaxoSmithKline, P.T.M. Severo Ochoa, Tres Cantos, Madrid 28760, Spain., Lafuente-Monasterio MJ; Tres Cantos Medicines Development Campus, GlaxoSmithKline, P.T.M. Severo Ochoa, Tres Cantos, Madrid 28760, Spain., Garcia BA; Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd., Bldg. 421, Philadelphia, Pennsylvania 19104, United States., Kafsack BFC; Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Avenue, W-705, New York, New York 10065, United States.; Biochemistry, Cell & Molecular Biology Graduate Program, Weill Cornell Medicine, 1300 York Avenue, W-705, New York, New York 10065, United States., Martinez ED; Department of Pharmacology, The University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, Texas 75390, United States.; Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, Texas 75390, United States.
Jazyk: angličtina
Zdroj: ACS infectious diseases [ACS Infect Dis] 2020 May 08; Vol. 6 (5), pp. 1058-1075. Date of Electronic Publication: 2020 Apr 24.
DOI: 10.1021/acsinfecdis.9b00455
Abstrakt: 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.
Databáze: MEDLINE
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