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

Grant number: 09/54325-2
Support type:Research Grants - Young Investigators Grants
Duration: December 01, 2010 - April 30, 2014
Field of knowledge:Biological Sciences - Biophysics
Principal Investigator:Carsten Wrenger
Grantee:Carsten Wrenger
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):13/17577-9 - Analysis of the ATCase catalysis within the amino acid metabolism of the human malaria parasite Plasmodium falciparum, BP.DD
12/12790-3 - Analysis of the haemoglobin catabolism of Plasmodium falciparum proliferation in genetically modified erythrocytes, BP.DR
12/12807-3 - Analysis of the redox status and its effect on the proliferation of Plasmodium falciparum in genetically different erythrocytes, BP.DR
11/13706-3 - Implications from pyridoxine kinase of Plasmodium falciparum and study if its spacer regions, BP.MS
10/20647-0 - Elucidation of vitamin B metabolism in the human malaria parasite plasmodium falciparum and their validation as a target for chemotherapy, BP.JP

Abstract

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)

Scientific publications (9)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
BOSCH, SORAYA S.; KRONENBERGER, THALES; MEISSNER, KAMILA A.; ZIMBRES, FLAVIA M.; STEGEHAKE, DIRK; IZUI, NATALIA M.; SCHETTERT, ISOLMAR; LIEBAU, EVA; WRENGER, CARSTEN. Oxidative Stress Control by Apicomplexan Parasites. BIOMED RESEARCH INTERNATIONAL, 2015. Web of Science Citations: 11.
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. Web of Science Citations: 1.
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. Web of Science Citations: 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. Web of Science Citations: 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. Web of Science Citations: 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. Web of Science Citations: 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. Web of Science Citations: 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. Web of Science Citations: 76.
ZIMBRES, FLAVIA M.; TARNOK, ATTILA; ULRICH, HENNING; WRENGER, CARSTEN. Aptamers: Novel Molecules as Diagnostic Markers in Bacterial and Viral Infections?. BIOMED RESEARCH INTERNATIONAL, 2013. Web of Science Citations: 22.

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