An Unusual Pyridine Nucleotide Accumulating in Erythrocytes: Its Identity, and Positive Correlation with Degree of Renal Failure

Abstract

We have investigated an unusual nucleotide that accumulates, with precursors, in the erythrocytes of patients in uraemia. This nucleotide is related chemically to the NAD breakdown product, N1-methyl-2-pyridone-5-carboxamide (Me2Py), found in high concentrations in the plasma of uraemic patients. Both Me2Py and the nucleotide accumulate to high concentrations in the blood during uraemia: our investigations of samples from renal out-patients have provided information on a plausible link between the two compounds.

A Novel Nucleotide Found in Human Erythrocytes, 4-Pyridone-3-carboxamide-1-β-d-ribonucleoside Triphosphate

“…These data indicate that the healthy human erythrocyte concentration of 4PYTP is significant, corresponding to ϳ2% of the ATP level. Massive accumulation of 4PYTP was observed in patients with renal failure, up to 10% of ATP on average or up to 30% in advanced chronic renal failure, which is consistent with our previous suggestions (7,8). Fig.…”

“…These results together with data from our earlier study (7,8) provide evidence for the pathway by which 4PYTP is formed in the erythrocytes. Because specific inhibitor totally blocked this process, nucleoside phosphorylation mediated by adenosine kinase is the most likely step leading to incorporation of 4PYR into the nucleotide pool.…”

“…However, the exact source and pathway leading to the formation of 4PYR in plasma is less certain. We suggested earlier that the activity of aldehyde oxidase is essential for generation of the 4PYR, as no 4PYTP accumulation was observed in an erythrocyte extract of a patient with molybdenum cofactor deficiency who developed chronic renal failure (7,8). Because aldehyde oxidase is not present in the erythrocytes (liver is the major site of its expression in humans (30)), formation of erythrocyte 4PYTP may depend on the provision of 4PYR into the circulation by the other organs, such as the liver.…”

“…Therefore, it was very surprising for us to note an unknown nucleoside triphosphate that was present at high levels in the erythrocytes of patients with renal failure but also at low concentrations in the erythrocytes of healthy subjects (7,8). A correlation between concentrations of this unknown nucleotide in erythrocytes and the plasma concentration of a nicotinamide catabolite N-methyl-2-pyridone-5-carboxamide (Met2PY) 2 suggested that both compounds could be related (7,8). However, further comparison of chemical properties indicated that this is not the case.…”

4-pyridone-3-carboxamide ribonucleoside triphosphate accumulating in erythrocytes in end stage renal failure originates from tryptophan metabolism

“…Nucleoside and base analysis in plasma by RPLC No identifiable precursor for 4PYTP was found in the plasma, suggesting initially that the nucleoside from which 4PYTP originates [14], must result from a precursor taken up rapidly from the plasma, or be formed within the erythrocyte. Alternatively, the precursor may be labile and broken down during the TCA acid extraction step.…”