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

Abstract

We recently identified an erythrocyte nucleotide accumulating in end-stage renal disease as 4-pyridone-3-carboxamide ribonucleotide triphosphate (4PYTP), a nucleotide never described previously. Plasma tryptophan concentration has been previously reported to be reduced in patients in chronic renal failure that is in turn associated with elevated precursors of tryptophan metabolism, including L -kynurenine and quinolinic acid, both of which have been implicated in the neurotoxic manifestations of chronic renal failure. Here we compare mean erythrocyte 4PYTP, and plasma tryptophan concentrations, in controls and four patient groups with renal impairment (10 per group) and confirmed a reduction in plasma tryptophan in patients on dialysis that corrected with renal transplantation. We found: An inverse correlation between plasma tryptophan and red cell 4PYTP concentrations (R(2)=0.44, P<0.001) when all patients were grouped together. Restoration of both tryptophan and 4PYTP concentrations to control values was only achieved following renal transplantation. 4PYTP was absent from erythrocytes in Molybdenum cofactor (MoCF) deficiency implicating aldehyde oxidase/dehydrogenase, a Molybdenum requiring enzyme. High 4PYTP erythrocyte concentrations in adenine or hypoxanthine-phosphoribosyltransferase deficient patients in severe uremia (113 microM and 103 microM), confirmed the lack of involvement of either enzyme in 4PYTP formation. We propose that 4PYTP is formed by a novel route involving the oxidation of the intermediates of NAD turnover from quinolinic acid by aldehyde oxidase.

Relationship between an increased serum kynurenine/tryptophan ratio and atherosclerotic parameters in hemodialysis patients

“…Increases in Kyn and its metabolites are also found in the brain tissue of uremic rats 5,6 . Accumulated Trp metabolite (4‐pyridone‐3‐carboxamide ribonucleotide triphosphate) is found in the erythrocytes in patients with end‐stage renal disease (ESRD) 7 . Indoleamine 2,3‐dioxygenase activity is also associated with graft survival in patients receiving kidney transplantation 8 …”

“…5,6 Accumulated Trp metabolite (4-pyridone-3-carboxamide ribonucleotide triphosphate) is found in the erythrocytes in patients with end-stage renal disease (ESRD). 7 Indoleamine 2,3dioxygenase activity is also associated with graft survival in patients receiving kidney transplantation. 8 Indoleamine 2,3-dioxygenase activity is demonstrated to correlate positively with carotid artery intima-medial thickness (CA-IMT) in general population.…”

Towards a platform for the metabonomic profiling of different strains of Drosophila melanogaster using liquid chromatography–Fourier transform mass spectrometry

“…Aldehyde oxidase is involved in tyrosine metabolism (gentisaldehyde to homogentisic acid), tryptophan metabolism (indole/hydroxyindole aldehydes to the corresponding acids) and pyridoxine metabolism (pyridoxal to pyridoxate). A good indicator of aldehyde oxidase levels is obtained by measuring N ‐methylpyridone carboxamide, which is formed by the action of aldehyde oxidase on N ‐methyl nicotinamide [27,28]. We have observed this metabolite in human plasma (Watson, Al Zweiri, Kamleh, Walker & Andrew, unpublished data), but were unable to observe it in either OR or mal .…”

Tryptophan in Molecular Hematopoiesis

“…Tryptophan levels in the cerebrospinal fl uid (CSF) of cerebral malaria children were linked to the hematological red blood cell parameters (Ebuehi et al 2009 ). 4-Pyridone-3-carboxamide ribonucleoside triphosphate accumulating in erythrocytes in end-stage renal failure originates from tryptophan metabolism (Laurence et al 2007 ).…”