Proteína multifuncional ADE2 como nexo entre vías de recuperación y síntesis de novo de nucleótidos

Abstract

Nucleosides and nucleotides have a key role in cell physiology being implicated in crucial processes such as DNA and RNA synthesis, cell signaling and metabolic regulation. Purine and pyrimidine nucleotide balance is required for cell homeostasis, being imbalance and nucleotide depletion associated with metabolic dysregulation and cancer development. Understanding the molecular mechanisms behind these events appears to be a suitable approach to uncover novel drug anticancer targets and, eventually, improve therapy. De novo nucleotide biosynthesis is a highly energetic expensive process tightly regulated at different levels. PAICS (phosphoribosylaminoimidazole carboxylase / phosphoribosylaminoimidazole succinocarboxamide synthetase) gene encodes the bifunctional enzyme ADE2, which catalyzes steps 6 and 7 of de novo purine nucleotide biosynthesis. This enzyme has been reported to have an important role in carcinogenesis. Here we have analyzed how PAICS is regulated when nucleoside availability disturbances are induced using HT-29 cell lines. PAICS expression appears to be modulated in a challenging situation when the inhibitions of de novo pyrimidine nucleotide biosynthesis and salvage pathways were combined. Moreover when cells were cultured in a nucleoside depleted medium we observed a regulation of human Concentrative Nucleoside Transporters (hCNTs) expression. This type of modulation suggests that extracellular nucleoside availability and de novonucleotide biosynthesis are metabolically interconnected.