Plasmodium falciparum glycogen synthase kinase-3: molecular model, expression, intracellular localisation and selective inhibitors
| Autor: | Laurent Meijer, Marie Knockaert, Aline Primot, Virginie Thomas, Christopher J. Richardson, Laurence H. Pearl, Christian Doerig, Ali Jafarshad, Denise Mattei, Conrad Kunick, Blandine Baratte, Pina Sallicandro, Pietro Alano, Daniel Parzy, Eliane Droucheau |
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| Přispěvatelé: | Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2003 |
| Předmět: |
Models
Molecular Erythrocytes Molecular Sequence Data Plasmodium falciparum Biophysics Gene Expression Biochemistry Analytical Chemistry Substrate Specificity 03 medical and health sciences Glycogen Synthase Kinase 3 0302 clinical medicine Axin Protein Cyclin-dependent kinase GSK-3 Gene expression Animals Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Amino Acid Sequence Enzyme Inhibitors Glycogen synthase Protein kinase A Molecular Biology Peptide sequence Phylogeny 030304 developmental biology 0303 health sciences biology Base Sequence Sequence Homology Amino Acid Recombinant Proteins 3. Good health Repressor Proteins 030220 oncology & carcinogenesis biology.protein Binding domain |
| Zdroj: | BBA-Biochimica et Biophysica Acta BBA-Biochimica et Biophysica Acta, Elsevier, 2004, 1697, pp.181-196 BBA-Biochimica et Biophysica Acta, 2004, 1697, pp.181-196 |
| ISSN: | 0006-3002 |
| Popis: | Worldwide increasing resistance of Plasmodium falciparum to common anti-malaria agents calls for the urgent identification of new drugs. Glycogen synthase kinase-3 (GSK-3) represents a potential screening target for the identification of such new compounds. We have cloned PfGSK-3, the P. falciparum gene homologue of GSK-3 beta. It encodes a 452-amino-acid, 53-kDa protein with an unusual N-terminal extension but a well-conserved catalytic domain. A PfGSK-3 tridimensional homology model was generated on the basis of the recently crystallised human GSK-3 beta. It illustrates how the regions involved in the active site, in substrate binding (P+4 phosphate binding domain) and in activity regulation are highly conserved. Recombinant PfGSK-3 phosphorylates GS-1, a GSK-3-specific peptide substrate, glycogen synthase, recombinant axin and the microtubule-binding protein tau. Neither native nor recombinant PfGSK-3 binds to axin. Expression and intracellular localisation of PfGSK-3 were investigated in the erythrocytic stages. Although PfGSK-3 mRNA is present in similar amounts at all stages, the PfGSK-3 protein is predominantly expressed at the early trophozoite stage. Once synthesized, PfGSK-3 is rapidly transported to the erythrocyte cytoplasm where it associates with vesicle-like structures. The physiological functions of PfGSK-3 for the parasite remain to be elucidated. A series of GSK-3 beta inhibitors were tested on both PfGSK-3 and mammalian GSK-3beta. Remarkably these enzymes show a partially divergent sensitivity to the compounds, suggesting that PfGSK-3 selective compounds might be identified. |
| Databáze: | OpenAIRE |
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