Evolution of the gene translation machinery and its applications to drug discovery

• Autores: Eva María Novoa Pardo
• Directores de la Tesis: Modesto Orozco López (dir. tes.), Lluís Ribas de Pouplana (dir. tes.)
• Lectura: En la Universitat de Barcelona ( España ) en 2012
• Idioma: inglés
• Tribunal Calificador de la Tesis: Manuel Antonio da Silva Santos (presid.), Baldomero Oliva Miguel (secret.), Luis Ballell Pages (voc.)
• Materias:
  • Ciencias de la vida
    • Genética
    • Biología molecular
  • Ciencias médicas
    • Patología
      • Parasitología
    • Farmacología
      • Evaluación de medicamentos
• Enlaces
  • Tesis en acceso abierto en:  TDX  Dipòsit Digital de la UB 
• Resumen

  • Gene translation is a central process in all cells, in which messenger RNA (mRNA) is decoded by the ribosome to produce a specific amino acid chain, that will later fold into an active protein. This process is facilitated by transfer RNAs (tRNAs), which carry the specific amino acids, and bind with its complementary anticodon sequences to that of the mRNA. The correct charging of the tRNA is catalyzed by aminoacyl-tRNA synthetases, and thus, are responsible for stablishing the genetic code. Despite the central role of tRNAs in protein translation, the connections between tRNA gene population dynamics and genome evolution have rarely been explored. In this work we have characterized the evolution of genomes through the study of its tRNA populations. We find that its evolution is linked to the appearance of diverse strategies to maximize translation efficiency. Indeed, these diverse strategies rise due to the appearance of two tRNA modification enzymes, which cause a selective enrichment of specific tRNA isoacceptors, and consequently, the phenomenon of codon usage bias. Furthermore, we have characterized with greater detail the gene translation machinery of Plasmodium falciparum, the most deadly form of the Plasmodium genus causing malaria. To decipher novel compounds that inhibit parasite growth, we have designed and tested several drug design strategies both in slico and in vitro, finding some promising molecules that kill the parasite without damaging human cells, and that show in vivo activity against P.yoelii-infected mice.