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Elucidation of vitamin B metabolism in the human malaria parasite Plasmodium falciparum and their validation as a target for chemotherapy

Processo: 09/54325-2
Linha de fomento:Auxílio à Pesquisa - Apoio a Jovens Pesquisadores
Vigência: 01 de dezembro de 2010 - 30 de abril de 2014
Área do conhecimento:Ciências Biológicas - Biofísica - Biofísica Celular
Pesquisador responsável:Carsten Wrenger
Beneficiário:Carsten Wrenger
Instituição-sede: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brasil
Bolsa(s) vinculada(s):13/17577-9 - Análise da catálise da ATCase no metabolismo de Plasmodium falciparum, BP.DD
12/12790-3 - Análise do catabolismo da hemoglobina na proliferação de Plasmodium falciparum em eritrócitos geneticamente modificados, BP.DR
12/12807-3 - Análise do estado redox e seu efeito sobre a proliferação de Plasmodium falciparum em eritrócitos geneticamente diferentes, BP.DR
11/13706-3 - Implicações estruturais de mutantes da piridoxina quinase de Plasmodium falciparum e investigação das suas regiões espaçadoras, BP.MS
10/20647-0 - Metabolismo de vitamina B no parasita da malária humana Plasmodium falciparum e a sua validação como alvo para quimioterapia, BP.JP
Assunto(s):Malária  Vitaminas  Plasmodium falciparum  Quimioterapia 


Pyridoxal phosphate (PLP) and thiamine pyrophosphate (TPP) are cofactors of essential enzymes that are ubiquitous in all organisms. Humans depend on the uptake of vitamins via their diet, whereas fungi, bacteria and plants synthesis these cofactors de novo, which was recently' also reported for the malaria parasite Plasmodium falciparum. Additionally to the de novo syntheses, salvage pathways for B6 and B1 have been identified in P. falciparum, which raises questions about the relevance of this dual vitamin provision and further about the possible role of B6 in quenching oxidative stress as reported for plants. However prior to uptake PLP and TPP need to be dephosphorylated which is proposed to be carried out by a secreted phosphatase. Further vitamins are not solely present within the cytosol, they need to be transported into organelles of the parasite, such as the mitochondrion and the apicoplast. Transportation processes of vitamin B1 will be analysed by keto-acid dehydrogenase complexes and organelle specific vitamin B6 acquisition will be investigated via the cysteine desulphurylase NifS and SufS required for iron-sulphur-cluster formation. Both proteins need an acceptor protein, which is proposed to be dually trafficked into both organelles. In an additional project the novel secreted proteins to the surface of the infected erythrocyte will be analysed for their necessity as well as for their trafficking by applying the SELEX technology, which will be carried out in collaboration with researchers at USP. (AU)

Publicações científicas (9)
(Referências obtidas automaticamente do Web of Science e do SciELO, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores)
KRONENBERGER, THALES; LUNEV, SERGEY; WRENGER, CARSTEN; GROVES, MATTHEW R. Purification, crystallization and preliminary X-ray diffraction analysis of pyridoxal kinase from Plasmodium falciparum (PfPdxK). ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS, v. 70, n. 11, p. 1550-1555, NOV 2014. Citações Web of Science: 0.
DREBES, JULIA; KUENZ, MADELEINE; PEREIRA, CLAUDIO A.; BETZEL, CHRISTIAN; WRENGER, CARSTEN. MRSA Infections: From Classical Treatment to Suicide Drugs. Current Medicinal Chemistry, v. 21, n. 15, p. 1809-1819, MAY 2014. Citações Web of Science: 12.
PEREIRA, C. A.; SAYE, M.; WRENGER, C.; MIRANDA, M. R. Metabolite Transporters in Trypanosomatid Parasites: Promising Therapeutic Targets But... How to Deal with Them?. Current Medicinal Chemistry, v. 21, n. 15, p. 1707-1712, MAY 2014. Citações Web of Science: 3.
KRONENBERGER, THALES; LINDNER, JASMIN; MEISSNER, KAMILA A.; ZIMBRES, FLAVIA M.; CORONADO, MONIKA A.; SAUER, FRANK M.; SCHETTERT, ISOLMAR; WRENGER, CARSTEN. Vitamin B6-Dependent Enzymes in the Human Malaria Parasite Plasmodium falciparum: A Druggable Target?. BIOMED RESEARCH INTERNATIONAL, 2014. Citações Web of Science: 9.
BEGUM, AFSHAN; DREBES, JULIA; KIKHNEY, ALEXEY; MUELLER, INGRID B.; PERBANDT, MARKUS; SVERGUN, DMITRI; WRENGER, CARSTEN; BETZEL, CHRISTIAN. Staphylococcus aureus thiaminase II: oligomerization warrants proteolytic protection against serine proteases. ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, v. 69, n. 12, p. 2320-2329, DEC 2013. Citações Web of Science: 1.
KRONENBERGER, THALES; SCHETTERT, ISOLMAR; WRENGER, CARSTEN. Targeting the vitamin biosynthesis pathways for the treatment of malaria. Future Medicinal Chemistry, v. 5, n. 7, p. 769-779, MAY 2013. Citações Web of Science: 4.
NDJONKA, DIEUDONNE; RAPADO, LUDMILA NAKAMURA; SILBER, ARIEL M.; LIEBAU, EVA; WRENGER, CARSTEN. Natural Products as a Source for Treating Neglected Parasitic Diseases. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 14, n. 2, p. 3395-3439, FEB 2013. Citações Web of Science: 74.
ZIMBRES, FLAVIA M.; TARNOK, ATTILA; ULRICH, HENNING; WRENGER, CARSTEN. Aptamers: Novel Molecules as Diagnostic Markers in Bacterial and Viral Infections?. BIOMED RESEARCH INTERNATIONAL, 2013. Citações Web of Science: 20.

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