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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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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]
Total Authors: 13
Affiliation:
[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
Total Affiliations: 5
Document type: Journal article
Source: SCIENTIFIC REPORTS; v. 6, FEB 26 2016.
Web of Science Citations: 6
Abstract

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)

FAPESP's process: 11/51295-5 - Functional genomics in Plasmodium
Grantee:Célia Regina da Silva Garcia
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 11/21442-6 - Synthetic and natural polymers applied to tissue engineering
Grantee:Luiz Henrique Catalani
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
Grantee:Glaucius Oliva
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC