Lligams funcionals i bioquímics entre els transportadors de nucleòsids i el metabolisme de nucleòtids

Abstract

Maintenance of balanced nucleotide pools is necessary for cellular homeostasis. The nucleotide content of the cell is determined by the uptake of nucleosides by specific transporters, the salvage pathway and de novo synthesis of purine and pyrimidine nucleotides. These pathways are highly regulated at different levels and likely to be controlled by mechanisms allowing some sort of coordination among them. In order to decipher possible functional links within this machinery, in this work we have explored the relationship between nucleoside transporters and other elements of nucleotide metabolism. We have studied the interaction and the possible functional link of the human concentrative nucleoside transporter 3 (CNT3) with ADK (adenosine kinase), SAMHD1 (sterile alpha-motif (SAM) and histidine-aspartate (HD) domain-containing protein 1) and QDPR (quinoid dihydropteridin reductase), all of them somehow related to nucleotide metabolism. Biochemical and functional validation of these interactions has evidenced the interconnection between CNT3 and the machinery implicated in nucleotide metabolism. Furthermore, nucleoside analogues are used in the treatment of cancer but they are often administered as pro-drugs. Their metabolic activation takes profit of different metabolic steps known to be implicated in nucleotide metabolism. Thus, changes in these pathways can be extremely relevant in determining drug activation and action in cancer therapy. Recently, combinations of the nucleoside analog Ara-C (cytarabine) and FMS-like tyrosine kinase (FLT3) inhibitors have been developed as first line treatments of acute myeloid leukemia (AML). We have observed that FLT3 positively correlates with enzymes implicated in Ara-C metabolism such as deoxycytidine kinase (dCK), 5’-nucleotidase cN-II and SAMHD1. We have also demonstrated a link among these elements associated with FLT3 inhibition which supports the possibility of coordinated regulation of different elements of the nucleotide metabolic network by this tyrosine kinase receptor. These observations also suggest that, to avoid chemoresistance, it is important to consider the schedule of administration of Ara-C and FLT3 inhibitors in the treatment of AML. Overall, this study provides novel evidence suggesting the existence of protein networks able to promote coordinate regulation of the machinery implicated in nucleotide metabolism.