000056815 001__ 56815
000056815 005__ 20200221144317.0
000056815 0247_ $$2doi$$a10.1038/srep33189
000056815 0248_ $$2sideral$$a96391
000056815 037__ $$aART-2016-96391
000056815 041__ $$aeng
000056815 100__ $$aSerrán-Aguilera, L.
000056815 245__ $$aPlasmodium falciparum Choline Kinase Inhibition Leads to a Major Decrease in Phosphatidylethanolamine Causing Parasite Death
000056815 260__ $$c2016
000056815 5060_ $$aAccess copy available to the general public$$fUnrestricted
000056815 5203_ $$aMalaria is a life-threatening disease caused by different species of the protozoan parasite Plasmodium, with P. falciparum being the deadliest. Increasing parasitic resistance to existing antimalarials makes the necessity of novel avenues to treat this disease an urgent priority. The enzymes responsible for the synthesis of phosphatidylcholine and phosphatidylethanolamine are attractive drug targets to treat malaria as their selective inhibition leads to an arrest of the parasite''s growth and cures malaria in a mouse model. We present here a detailed study that reveals a mode of action for two P. falciparum choline kinase inhibitors both in vitro and in vivo. The compounds present distinct binding modes to the choline/ethanolamine-binding site of P. falciparum choline kinase, reflecting different types of inhibition. Strikingly, these compounds primarily inhibit the ethanolamine kinase activity of the P. falciparum choline kinase, leading to a severe decrease in the phosphatidylethanolamine levels within P. falciparum, which explains the resulting growth phenotype and the parasites death. These studies provide an understanding of the mode of action, and act as a springboard for continued antimalarial development efforts selectively targeting P. falciparum choline kinase.
000056815 536__ $$9info:eu-repo/grantAgreement/ES/MICINN/CTQ2013-44367-C2-2-P$$9info:eu-repo/grantAgreement/EC/FP7/283570/EU/Transnational access and enhancement of integrated Biological Structure determination at synchrotron X-ray radiation facilities/BIOSTRUCT-X$$9info:eu-repo/grantAgreement/ES/DGA/B89
000056815 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000056815 590__ $$a4.259$$b2016
000056815 591__ $$aMULTIDISCIPLINARY SCIENCES$$b10 / 63 = 0.159$$c2016$$dQ1$$eT1
000056815 592__ $$a1.691$$b2016
000056815 593__ $$aMultidisciplinary$$c2016$$dQ1
000056815 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000056815 700__ $$aDenton, H.
000056815 700__ $$aRubio-Ruiz, B.
000056815 700__ $$aLópez-Gutiérrez, B.
000056815 700__ $$aEntrena, A.
000056815 700__ $$aIzquierdo, L.
000056815 700__ $$aSmith, T.K.
000056815 700__ $$aConejo-García, A.
000056815 700__ $$0(orcid)0000-0002-3122-9401$$aHurtado-Guerrero, R.$$uUniversidad de Zaragoza
000056815 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000056815 773__ $$g6 (2016), 33189 [12 pp]$$pSci. rep.$$tSCIENTIFIC REPORTS$$x2045-2322
000056815 8564_ $$s1252750$$uhttps://zaguan.unizar.es/record/56815/files/texto_completo.pdf$$yVersión publicada
000056815 8564_ $$s105214$$uhttps://zaguan.unizar.es/record/56815/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000056815 909CO $$ooai:zaguan.unizar.es:56815$$particulos$$pdriver
000056815 951__ $$a2020-02-21-13:39:32
000056815 980__ $$aARTICLE