Biliverdin targets enolase and eukaryotic initiation factor 2 (eIF2 alpha) to reduce the growth of intraerythrocytic development of the malaria parasite Plasmodium falciparum

Autor(es):Mostrar menos -

Alves, Eduardo ^{[1, 2]} ; Maluf, Fernando V. ^[3] ; Bueno, Vania B. ^[4] ; Guido, Rafael V. C. ^[3] ; Oliva, Glaucius ^[3] ; Singh, Maneesh ^{[1, 2]} ; Scarpelli, Pedro ^{[1, 2]} ; Costa, Fahyme ^{[1, 2]} ; Sartorello, Robson ^[2] ; Catalani, Luiz H. ^[4] ; Brady, Declan ^[5] ; Tewari, Rita ^[5] ; Garcia, Celia R. S. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Parasitol, BR-05508 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Biociencias, Dept Fisiol, Nucleo Pesquisa Sinalizacao Celular Patogenohospe, BR-05508 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Inst Fis Sao Carlos, Ctr Pesquisa & Inovacao Biodiversidade & Farmacos, BR-05508 Sao Paulo - Brazil

^[4] Univ Sao Paulo, Inst Quim, Dept Quim Fundamental, BR-05508 Sao Paulo - Brazil

^[5] Univ Nottingham, Sch Life Sci, Nottingham NG7 2RD - England

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 6, FEB 26 2016.
• Citações Web of Science: 6

Resumo

In mammals, haem degradation to biliverdin (BV) through the action of haem oxygenase (HO) is a critical step in haem metabolism. The malaria parasite converts haem into the chemically inert haemozoin to avoid toxicity. We discovered that the knock-out of HO in P. berghei is lethal; therefore, we investigated the function of biliverdin (BV) and haem in the parasite. Addition of external BV and haem to P. falciparum-infected red blood cell (RBC) cultures delays the progression of parasite development. The search for a BV molecular target within the parasites identified P. falciparum enolase (Pf enolase) as the strongest candidate. Isothermal titration calorimetry using recombinant full-length Plasmodium enolase suggested one binding site for BV. Kinetic assays revealed that BV is a non-competitive inhibitor. We employed molecular modelling studies to predict the new binding site as well as the binding mode of BV to P. falciparum enolase. Furthermore, addition of BV and haem targets the phosphorylation of Plasmodium falciparum eIF2 alpha factor, an eukaryotic initiation factor phosphorylated by eIF2 alpha kinases under stress conditions. We propose that BV targets enolase to reduce parasite glycolysis rates and changes the eIF2 alpha phosphorylation pattern as a molecular mechanism for its action. (AU)

• Processo FAPESP: 11/51295-5 - Genômica funcional em Plasmodium
• Beneficiário: Célia Regina da Silva Garcia
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 11/21442-6 - Polímeros sintéticos e naturais aplicados à engenharia de tecido
• Beneficiário: Luiz Henrique Catalani
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
• Beneficiário: Glaucius Oliva
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs