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Doctoral Thesis
DOI
10.11606/T.42.2018.tde-22022018-135411
Document
Author
Full name
Raquel Maria Simão Gurge
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2017
Supervisor
Committee
Katzin, Alejandro Miguel (President)
Albuquerque, Cristina Northfleet de
Silveira Filho, José Franco da
Takahashi, Anita Hilda Straus
Toledo, Erika Suzuki de
Title in Portuguese
Estudo da via de heme farnesilado e dos inibidores desta via em estágios intraeritrocitários de P. falciparum.
Keywords in Portuguese
Plasmodium falciparum
Farnesilação
Heme O
Isoprenoides
Abstract in Portuguese
O desenvolvimento de antimaláricos é necessario pois, há linhagens de Plasmodium resistentes às drogas em uso e um alvo importante é a via de isoprenoides. Importantes alvos derivados desta via são: heme O já que, há antimaláricos relacionados ao heme; e a giberilina pois, há inibidores desta que não são prejudiciais ao homem. Inabenfide (INA) e uniconazol-P (UNP) inibem a biossíntese de giberilina em plantas e o crescimento de P. falciparum. Inicialmente, identificamos no parasita genes homólogos para a síntese de heme O e A, cox10 e 15, que codificam as enzimas HOS e HAS. Parasitas transgênicos com HOS e HAS marcados com GFP permitiram identificar a localização de cox10 no núcleo e de cox15 na mitocôndria. Identificamos heme O por marcações metabólicas e espectrometria de massa. Entretanto, não identificamos heme A e giberelina. INA e UNP diminuem a biossíntese de heme O e a parasitemia, observado por oxido-redução e marcação metabólica, o que torna a sintese de heme O um interessante alvo para antimaláricos.
Title in English
Study of the farnesylated heme synthesis pathway in intra-erythrocyte stages of P. falciparum and inhibitors of this pathway.
Keywords in English
Plasmodium falciparum
Farnesylation
Heme O
Isoprenoids
Abstract in English
The development of antimalarials is necessary because there are Plasmodium strains resistant to the drugs in use and an important target is the isoprenoid pathway. Targets derived from the isoprenoid pathway are: heme O as there are antimalarial drugs related to heme; And gibberillin, because there are inhibitors which are not harmful to man. Inabenfide (INA) and uniconazole-P (UNP) inhibit biosynthesis of gibberillin in plants and of growth the P. falciparum. Initially, we identified in P. falciparum genes homologous to cox10 and 15 encoding the enzymes (HOS and HAS) for synthesis of heme O and A. We created transgenic parasite lines which had HOS and HAS tagged to GFP. These revealed that the subcellular location of cox10 is in the nucleus and of cox15 in mitochondria. We identified heme O by metabolic labeling and mass spectrometry. However, no heme A or gibberellin was detected. INA and UNP decreased heme O biosynthesis and parasitemia as observed by oxido-reduction and metabolic labeling. Our data point to heme O as an important target for antimalarials.
 
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Release Date
2020-02-22
Publishing Date
2018-02-22
 
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