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Master's Dissertation
DOI
10.11606/D.42.2011.tde-05082011-105023
Document
Author
Full name
Rodrigo Antonio Ceschini Sussmann
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2011
Supervisor
Committee
Katzin, Alejandro Miguel (President)
Daffre, Sirlei
Kato, Massuo Jorge
Title in Portuguese
Biossíntese de vitamina E nos estágios intraeritrocitários de P. falciparum.
Keywords in Portuguese
Plasmodium
Antimaláricos
Espectrometria de massas
Malária
Vitamina E
Abstract in Portuguese
O estudo da biossíntese de isoprenóides em P. falciparum por meio da via 2C-metil-D-eritritol-4-fosfato (MEP) é apontado como possível alvo terapêutico, visto a via ser ausente em humanos. Foi descrito que nos estágios intraeritrocitários de P. falciparum a via essencial de biossíntese de isoprenóides é a via MEP. As vias do Chiquimato e MEP são precursoras da biossíntese de vitamina E e ambas já foram descritas em P. falciparum. É sugerido que a biossíntese de vitamina E possa ocorrer no parasita, representando um possível alvo para o desenvolvimento de novas drogas antimaláricas. Empregando marcações metabólicas com precursores radioativos, três diferentes métodos de RP-HPLC e análises por espectrometria de massas confirmamos a biossíntese de vitamina E nos três estágios intraeritrocíticos do parasita. O tratamento com ácido úsnico, mostrou inibição dessa biossíntese no estágio esquizonte e do crescimento do parasita. Demonstramos por meio de uma sonda fluorescente, ácido Parinárico, que a vitamina E atua como antioxidante lipofílico, protegendo a lipoperoxidação. Esses resultados não só contribuem para a compreensão da biologia de P. falciparum, mas também elucidam partes das vias MEP e do Chiquimato que podem servir como alvos terapêuticos.
Title in English
Vitamin E biosynthesis in intraerythrocytic stages of Plasmodium falciparum.
Keywords in English
Plasmodium
Antimalarials
Malaria
Mass spectrometry
Vitamin E
Abstract in English
The study of isoprenoid biosynthesis in Plasmodium falciparum by 2C-methyl-D-erythritol-4-phosphate pathway (MEP) it is presented as a therapeutic target once that it is absent in humans. It was found in intraerythrocytic stages of P. falciparum the biosynthesis of isoprenoids by the MEP pathway. The shikimate and MEP pathways are the precursors of biosynthesis of vitamin E and both pathways have already been described in P. falciparum. It is suggested that the biosynthesis of vitamin E might occur in the parasite, representing a possible target for developing new antimalarial drugs. Using metabolic labelling with radiolabelled precursors, three different methods of RP-HPLC and mass spectrometry analyses confirmed the biosynthesis of vitamin E in the three intraerythrocytic stages of parasite. The treatment with usnic acid showed an inhibition of this biosynthesis and of the growth of parasite. We demonstrated by means of a fluorescent probe, the acid Parinaric, that vitamin E acts as a lipophilic antioxidant protecting the membrane of lipoperoxidation. These findings not only contribute to the current understanding of P. falciparum biology but shed light on a pathway that could serve as a chemotherapeutic target.
 
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Publishing Date
2011-08-24
 
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