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Toxins 2011, 3(6), 520-537; doi:10.3390/toxins3060520
Article

4-Pyridone-3-carboxamide-1-β-d-ribonucleoside Triphosphate (4PyTP), a Novel NAD+ Metabolite Accumulating in Erythrocytes of Uremic Children: A Biomarker for a Toxic NAD+ Analogue in Other Tissues?

1, 2
, 2,†, 3
, 3
 and 1,*
1 University College London Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK 2 Purine Research Laboratory, Chemical Pathology Department, St Thomas’ Hospital, London SE1 7EH, UK 3 Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland Deceased on 2 April 2010.
* Author to whom correspondence should be addressed.
Received: 25 March 2011 / Revised: 13 May 2011 / Accepted: 31 May 2011 / Published: 7 June 2011
(This article belongs to the Special Issue Uremic Toxins)
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Abstract

We have identified a novel nucleotide, 4-pyridone 3/5-carboxamide ribonucleoside triphosphate (4PyTP), which accumulates in human erythrocytes during renal failure. Using plasma and erythrocyte extracts obtained from children with chronic renal failure we show that the concentration of 4PyTP is increased, as well as other soluble NAD+ metabolites (nicotinamide, N1-methylnicotinamide and 4Py-riboside) and the major nicotinamide metabolite N1-methyl-2-pyridone-5-carboxamide (2PY), with increasing degrees of renal failure. We noted that 2PY concentration was highest in the plasma of haemodialysis patients, while 4PyTP was highest in erythrocytes of children undergoing peritoneal dialysis: its concentration correlated closely with 4Py-riboside, an authentic precursor of 4PyTP, in the plasma. In the dialysis patients, GTP concentration was elevated: similar accumulation was noted previously, as a paradoxical effect in erythrocytes during treatment with immunosuppressants such as ribavirin and mycophenolate mofetil, which deplete GTP through inhibition of IMP dehydrogenase in nucleated cells such as lymphocytes. We predict that 4Py-riboside and 4Py-nucleotides bind to this enzyme and alter its activity. The enzymes that regenerate NAD+ from nicotinamide riboside also convert the drugs tiazofurin and benzamide riboside into NAD+ analogues that inhibit IMP dehydrogenase more effectively than the related ribosides: we therefore propose that the accumulation of 4PyTP in erythrocytes during renal failure is a marker for the accumulation of a related toxic NAD+ analogue that inhibits IMP dehydrogenase in other cells.
Keywords: uremia; erythrocytes; pyridone; NAD+; 4-pyridone 3/5-carboxamide ribonucleoside triphosphate (4PyTP); nicotinamide riboside (NR); IMP dehydrogenase; HPLC uremia; erythrocytes; pyridone; NAD+; 4-pyridone 3/5-carboxamide ribonucleoside triphosphate (4PyTP); nicotinamide riboside (NR); IMP dehydrogenase; HPLC
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Synesiou, E.; Fairbanks, L.D.; Simmonds, H.A.; Slominska, E.M.; Smolenski, R.T.; Carrey, E.A. 4-Pyridone-3-carboxamide-1-β-d-ribonucleoside Triphosphate (4PyTP), a Novel NAD+ Metabolite Accumulating in Erythrocytes of Uremic Children: A Biomarker for a Toxic NAD+ Analogue in Other Tissues? Toxins 2011, 3, 520-537.

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