The Novel Nucleotide 4KNTP, in High Concentrations in Erythrocytes of Renal Failure Children: a Comparison with Accumulation of Other Putative Precursors in the Plasma

Carrey, Elizabeth A.; Synesiou, Elena; Simmonds, H. Anne; Fairbanks, L D

doi:10.1080/15257770600890947

Cited by 2 publications

(5 citation statements)

References 7 publications

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“…A peak eluting at 3.3 to 3.5 min from our anion exchange HPLC system has now been identified as 2PY (it was erroneously reported earlier [6] to be the ribonucleoside related to 4PyTP) and has been found in the erythrocytes of all dialysis patients (Figure 1), but in only a small number of erythrocyte extracts from non-dialysed patients. In dialysis patients, where the concentration of 2PY in the plasma was already above 30 μM (Table 2), the concentration of 2PY in the red cells of each patient correlated closely with the external concentration in the plasma ( r = 0.845).…”

Section: Resultsmentioning

confidence: 72%

“…A representative clinical sample from a MoCo-deficient infant is illustrated in reference 3. In humans N 1 -methylnicotinamide is converted to 2PY in great excess over 4PY [6,25], whereas the reverse is true in other mammals. Even when 4Py-riboside is found in significant concentrations in the plasma of renal failure patients, especially those with high levels of 4PyTP, we have not detected a 2-pyridone analogue.…”

Section: Resultsmentioning

confidence: 99%

“…The nucleotide elutes after ATP in our anion-exchange HPLC profiles, and has a characteristic UV absorption spectrum similar but not identical to that of 2PY [4]. The natural compound (tentatively named 2PyTP [3]) has now been identified unequivocally as the N 1 -riboside triphosphate of 4-pyridone 3/5-carboxamide (4PyTP) [5], earlier also named by us as 4-ketonicotinamide riboside triphosphate or 4KNTP [6]. …”

Section: Introductionmentioning

confidence: 99%

“…A preliminary report of some of these data has been presented [6]. We have subsequently measured several putative biosynthetic precursors in plasma and erythrocytes, and it is now clear that 2PY and 4PyTP are derived from NAD + by distinct degradation pathways.…”

Section: Introductionmentioning

confidence: 99%

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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?

Synesiou

Fairbanks

Simmonds

et al. 2011

Toxins

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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.

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Section: Resultsmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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?

Synesiou

Fairbanks

Simmonds

et al. 2011

Toxins

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“…The ribosylated form of the pyridone carboxamides, 4-pyridone-3-carboxamide riboside (4PYR), and 6-pyridone-3-carboxamide riboside also known as 2-pyridone-5-carboxamide riboside (6PYR), are also detected in urine [5]. In blood, these ribosylated pyridones are mostly present intracellularly in their triphosphorylated (4PYR-TP and 6PYR-TP) [6,7] or adenine dinucleotidic forms [8]. N-Methyl-2-pyridone-3-carboxamide (Me-2PY) and 2-pyridone-3-carboxamide riboside (2PYR) are the least prominent pyridones in the literature, as they are much less often detected in biological samples [9].…”

Section: Introductionmentioning

confidence: 99%

The Biochemical Pathways of Nicotinamide-Derived Pyridones

Hayat

Sonavane

Makarov

et al. 2021

IJMS

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As catabolites of nicotinamide possess physiological relevance, pyridones are often included in metabolomics measurements and associated with pathological outcomes in acute kidney injury (AKI). Pyridones are oxidation products of nicotinamide, its methylated form, and its ribosylated form. While they are viewed as markers of over-oxidation, they are often wrongly reported or mislabeled. To address this, we provide a comprehensive characterization of these catabolites of vitamin B3, justify their nomenclature, and differentiate between the biochemical pathways that lead to their generation. Furthermore, we identify an enzymatic and a chemical process that accounts for the formation of the ribosylated form of these pyridones, known to be cytotoxic. Finally, we demonstrate that the ribosylated form of one of the pyridones, the 4-pyridone-3-carboxamide riboside (4PYR), causes HepG3 cells to die by autophagy; a process that occurs at concentrations that are comparable to physiological concentrations of this species in the plasma in AKI patients.

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The Novel Nucleotide 4KNTP, in High Concentrations in Erythrocytes of Renal Failure Children: a Comparison with Accumulation of Other Putative Precursors in the Plasma

Cited by 2 publications

References 7 publications

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?

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?

The Biochemical Pathways of Nicotinamide-Derived Pyridones

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