Metabolic pathway of 4-pyridone-3-carboxamide-1β-d-ribonucleoside and its effects on cellular energetics.
4-pirydone-3-carboxamide-1β-d-ribonucleoside (4PYR) is an endogenous nucleoside that could be converted to triphosphates, diphosphates, monophosphates and an analogue of NAD - 4PYRAD. Elevated level of these compounds have been reported in chronic renal failure, cancer and active HIV infection. However, little is known about the effect on cell functionality and the metabolic pathways. This study tested effects of 4PYR in different cell types on nucleotide, energy metabolism and clarified enzymes that are involved in conversions of 4PYR. We have found that human neuroblastoma cells, human malignant melanoma cells, human adipose-derived stem cells, human bone marrow-derived stem cells, human dermal microvascular endothelial cells and human embryonic kidney cells, were capable to convert 4PYR into its derivatives. This was associated with deterioration of cellular energetics. Incubation with 4PYR did not affect mitochondrial function, but decreased glycolytic rate (as measured by extracellular acidification) in endothelial cells. Silencing of adenosine kinase, cytosolic 5'-nucleotidase II and nicotinamide nucleotide adenylyltransferase 3, blocked metabolism of 4PYR. Incubation of endothelial cells with 4PYR decreased AMP deaminase activity by 40%. The main finding of this paper is that human cells (including cancer type) are capable of metabolizing 4PYR that lead to deterioration of energy metabolism, possibly as the consequence of inhibition of glycolysis. This study, it was also found that several enzymes of nucleotide metabolism could also contribute to the 4PYRconversions.
Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland.
Iwona
I
Pelikant-Malecka
Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland.
Ewa
E
Kaniewska-Bednarczuk
Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland.
Sylwia
S
Szrok
Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland; Structural Heart Research Lab, Division of Cardiothoracic Surgery, Emory University, 380-B Northyards Blvd, Atlanta, 30308 GA, USA.
Alicja
A
Sielicka
Department of General Surgery, Department of Emergency Medicine, Medical University of Gdansk, Smoluchowskiego 17, 80-211 Gdansk, Poland.
Maciej
M
Sledzinski
Department of Organic Chemistry, Medical University of Gdansk, Al. Gen. J. Hallera 107, 80-416 Gdansk, Poland.
Czesława
C
Orlewska
Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland.
Ryszard T
RT
Smolenski
Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland. Electronic address: eslom@gumed.edu.pl.
Ewa M
EM
Slominska
D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009705:Nucleosides / Q000378:metabolism* / Q000494:pharmacology*; D011728:Pyridones / Q000378:metabolism* / Q000494:pharmacology*
C554932:4-pyridone-3-carboxamide-1-ribonucleoside; D009705:Nucleosides; D011728:Pyridones
4-pirydone-3-carboxamide-1β-dribonucleoside (4PYR); Endothelial cells; Metabolism; Nucleotides