Key role of uridine kinase and uridine phosphorylase in the homeostatic regulation of purine and pyrimidine salvage in brain.
Uridine, the major circulating pyrimidine nucleoside, participating in the regulation of a number of physiological processes, is readily uptaken into mammalian cells. The balance between anabolism and catabolism of intracellular uridine is maintained by uridine kinase, catalyzing the first step of UTP and CTP salvage synthesis, and uridine phosphorylase, catalyzing the first step of uridine degradation to beta-alanine in liver. In the present study we report that the two enzymes have an additional role in the homeostatic regulation of purine and pyrimidine metabolism in brain, which relies on the salvage synthesis of nucleotides from preformed nucleosides and nucleobases, rather than on the de novo synthesis from simple precursors. The experiments were performed in rat brain extracts and cultured human astrocytoma cells. The rationale of the reciprocal regulation of purine and pyrimidine salvage synthesis in brain stands (i) on the inhibition exerted by UTP and CTP, the final products of the pyrimidine salvage pathway, on uridine kinase and (ii) on the widely accepted idea that pyrimidine salvage occurs at the nucleoside level (mostly uridine), while purine salvage is a 5-phosphoribosyl-1-pyrophosphate (PRPP)-mediated process, occurring at the nucleobase level. Thus, at relatively low UTP and CTP level, uptaken uridine is mainly anabolized to uridine nucleotides. On the contrary, at relatively high UTP and CTP levels the inhibition of uridine kinase channels uridine towards phosphorolysis. The ribose-1-phosphate is then transformed into PRPP, which is used for purine salvage synthesis.
Balestri
Francesco
F
Dipartimento di Biologia, Unità di Biochimica, Università di Pisa, Via S. Zeno 51, 56100 Pisa, Italy.
Barsotti
Catia
C
Lutzemberger
Ludovico
L
Camici
Marcella
M
Ipata
Piero Luigi
PL
D000818:Animals; D001921:Brain / Q000201:enzymology*; D001923:Brain Chemistry / Q000502:physiology; D003570:Cytidine Triphosphate / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D008297:Male; D009696:Nucleic Acids / Q000378:metabolism; D009705:Nucleosides / Q000378:metabolism; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D011687:Purines / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012267:Ribosemonophosphates / Q000378:metabolism; D013347:Subcellular Fractions; D014407:Tumor Cells, Cultured; D014541:Uridine Kinase / Q000378:metabolism*; D014543:Uridine Phosphorylase / Q000378:metabolism*; D014544:Uridine Triphosphate / Q000378:metabolism
D009696:Nucleic Acids; D009705:Nucleosides; D011687:Purines; D011743:Pyrimidines; D012267:Ribosemonophosphates; C031154:ribose 1-phosphate; D003570:Cytidine Triphosphate; D010754:Phosphoribosyl Pyrophosphate; D014543:Uridine Phosphorylase; D014541:Uridine Kinase; D014544:Uridine Triphosphate