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Evaluation of the involvement of eIF5A in the secretory pathway in Saccharomyces cerevisiae

Grant number: 11/21232-1
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): March 01, 2012
Effective date (End): January 31, 2013
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Cleslei Fernando Zanelli
Grantee:Leonardo Biancolino Marino
Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil


The probable translation initiation factor 5A (eIF5A) is highly conserved from archaea to mammals and undergoes a post-translational modification unique and essential called hipusination. Although the function of eIF5A as a translation initiation factor has never been clearly demonstrated, recent results from our laboratory strengthen its involvement in protein synthesis and suggest that its role is more related to the elongation step of translation. Studies also related eIF5A with cell proliferation and transition G1/S cell cycle, suggesting its involvement in translation of specific proteins that act directly on cell cycle progression. Additionally, it was shown that TIF51A is synthetically lethal with the gene YPT1, which encodes the protein Ypt1 responsible for vesicular transport of proteins from the Endoplasmic Reticulum (ER) to Golgi. The discovery of the genetic interaction between YPT1 and TIF51A suggests a connection between translation and the secretory pathway, essential for the process of budding and cell cycle progression in yeast. Moreover, recent data from our laboratory, unpublished, suggest the involvement of eIF5A in the secretory pathway by acting on the translocation of proteins to the ER via co-translational. To confirm this hypothesis, we intend to evaluate the role of eIF5A in the way of co-translational translocation, by tests of genetic interactions between TIF51A mutants and mutants of genes that encoding proteins that act in this way, for example mutants of the Sec complex (translocon), SRP (Signal Recognition Particle) and SRP´s receptors located in the ER membrane. In addition, we intend to conduct trials of co-purification of ribosomes associated with the translation machinery components, trying to analyze the differences between the wild and those strains that have mutations in the gene for eIF5A. Finally, it proposes to carry out proteomic analysis of cell wall components for mutants of eIF5A and deoxy-hipusine synthase, comparing the protein content of the wall of these mutants with that of the wild strain, so to better understand the phenotypes of mutants and how hipusinated eIF5A affects the translation associated with the secretory pathway. (AU)

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Scientific publications (6)
(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)
LARROUY-MAUMUS, GERALD; MARINO, LEONARDO B.; MADDURI, ASHOKA V. R.; RAGAN, T. J.; HUNT, DEBBIE M.; BASSANO, LUCREZIA; GUTIERREZ, MAXIMILIANO G.; MOODY, D. BRANCH; PAVAN, FERNANDO R.; DE CARVALHO, LUIZ PEDRO S.. Cell-Envelope Remodeling as a Determinant of Phenotypic Antibacterial Tolerance in Mycobacterium tuberculosis. ACS INFECTIOUS DISEASES, v. 2, n. 5, p. 352-360, . (13/14957-5, 11/21232-1)
MORI, GIORGIA; CHIARELLI, LAURENT R.; ESPOSITO, MARTA; MAKAROV, VADIM; BELLINZONI, MARCO; HARTKOORN, RUBEN C.; DEGIACOMI, GIULIA; BOLDRIN, FRANCESCA; EKINS, SEAN; LOPES RIBEIRO, ANA LUISA DE JESUS; et al. Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG. CHEMISTRY & BIOLOGY, v. 22, n. 7, p. 917-927, . (11/21232-1)
ABD EL-WAHAB, HEND A. A.; ACCIETTO, MAURO; MARINO, LEONARDO B.; MCLEAN, KIRSTY J.; LEVY, COLIN W.; ABDEL-RAHMAN, HAMDY M.; EL-GENDY, MAHMOUD A.; MUNRO, ANDREW W.; ABORAIA, AHMED S.; SIMONS, CLAIRE. Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics. Bioorganic & Medicinal Chemistry, v. 26, n. 1, p. 161-176, . (11/21232-1)
TABAN, ISMAIL M.; ELSHIHAWY, HOSAM E. A. E.; TORUN, BEYZA; ZUCCHINI, BENEDETTA; WILLIAMSON, CLARE J.; ALTUWAIRIGI, DANIA; NGU, ADELINE S. T.; MCLEAN, KIRSTY J.; LEYY, COLIN W.; SOOD, SAKSHI; et al. Novel Aryl Substituted Pyrazoles as Small Molecule Inhibitors of Cytochrome P450 CYP121A1: Synthesis and Antimycobacterial Evaluation. Journal of Medicinal Chemistry, v. 60, n. 24, p. 10257-10267, . (11/21232-1)
KAVANAGH, MADELINE E.; COYNE, ANTHONY G.; MCLEAN, KIRSTY J.; JAMES, GUY G.; LEVY, COLIN W.; MARINO, LEONARDO B.; DE CARVALHO, LUIZ PEDRO S.; CHAN, DANIEL S. H.; HUDSON, SEAN A.; SURADE, SACHIN; et al. Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors. Journal of Medicinal Chemistry, v. 59, n. 7, p. 3272-3302, . (11/21232-1)
RODRIGUEZ ARCE, ESTEBAN; FLORENCIA MOSQUILLO, M.; PEREZ-DIAZ, LETICIA; ECHEVERRIA, GUSTAVO A.; PIRO, OSCAR E.; MERLINO, ALICIA; LAURA COITINO, E.; MARINGOLO RIBEIRO, CAMILA; LEITE, CLARICE Q. F.; PAVAN, FERNANDO R.; et al. Aromatic amine N-oxide organometallic compounds: searching for prospective agents against infectious diseases. DALTON TRANSACTIONS, v. 44, n. 32, p. 14453-14464, . (11/21232-1)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
MARINO, Leonardo Biancolino. Characterization of furoxan derivative compounds as efflux pump inhibitors in Mycobacterium tuberculosis and study of the efflux and halotolerance influence in the resistance profiles of the bacillus. 2016. Doctoral Thesis - Universidade Estadual Paulista (Unesp). Faculdade de Ciências Farmacêuticas. Araraquara Araraquara.

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