Metabolism of 4-Pyridone-3-Carboxamide-1-ß-D- Ribonucleoside Triphosphate and Its Nucleoside Precursor in the Erythrocytes

Słomińska, Ewa M.; Orlewska, Czesława; Yuen, Ada H. Y.; Osman, Lana; Romaszko, Paweł; Sokołowska, Ewa; Foks, Henryk; Simmonds, H. Anne; Yacoub, Magdi H.; Smolenski, Ryszard T.

doi:10.1080/15257770802146452

Cited by 17 publications

(23 citation statements)

References 3 publications

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“…It has previously been demonstrated that 4Py-riboside is taken up into intact human erythrocytes in vitro in a reaction carried out by adenosine kinase since it is inhibited by 5'-iodotubericidin, with a net consumption of ATP, and is rapidly converted to the mononucleotide and 4PyTP [ 45 ]. The erythrocyte samples in this study showed a very high accumulation of 4PyTP and 4PyDP, reflecting the much longer timescale and equilibrium within cells obtained in vivo .…”

Section: Resultsmentioning

confidence: 99%

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: 99%

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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“…4PYR is synthesized with AO involvement primarily in the liver, but it has also been shown that AO is overexpressed in malignant tumors, including breast cancer 16 , 19 . Some 4PYR is distributed to erythrocytes, in which it is rapidly phosphorylated 15 . 4PYR nucleoside phosphorylation into 4PYMP was found to be faster than its subsequent conversion to 4PYTP.…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that aldehyde oxidase (AO), the molybdenum cofactor-dependent enzyme, plays a role in 4PYR production by converting nicotinamide riboside 14 . It has also been indicated that adenosine kinase could be responsible for 4PYMP formation 15 . Moreover, earlier data demonstrated the potential involvement of cytosolic 5′-nucleotidase in the degradation of 4PYMP to 4PYR 16 .…”

Section: Introductionmentioning

confidence: 99%

An unusual nicotinamide derivative, 4-pyridone-3-carboxamide ribonucleoside (4PYR), is a novel endothelial toxin and oncometabolite

Mierzejewska

Kunc

Zabielska-Kaczorowska

et al. 2021

Exp Mol Med

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Our recent studies identified a novel pathway of nicotinamide metabolism that involves 4-pyridone-3-carboxamide-1-β-D-ribonucleoside (4PYR) and demonstrated its endothelial cytotoxic effect. This study tested the effects of 4PYR and its metabolites in experimental models of breast cancer. Mice were divided into groups: 4T1 (injected with mammary 4T1 cancer cells), 4T1 + 4PYR (4PYR-treated 4T1 mice), and control, maintained for 2 or 21 days. Lung metastasis and endothelial function were analyzed together with blood nucleotides (including 4PYR), plasma amino acids, nicotinamide metabolites, and vascular ectoenzymes of nucleotide catabolism. 4PYR metabolism was also evaluated in cultured 4T1, MDA-MB-231, MCF-7, and T47D cells. An increase in blood 4PYR in 4T1 mice was observed at 2 days. 4PYR and its metabolites were noticed after 21 days in 4T1 only. Higher blood 4PYR was linked with more lung metastases in 4T1 + 4PYR vs. 4T1. Decreased L-arginine, higher asymmetric dimethyl-L-arginine, and higher vascular ecto-adenosine deaminase were observed in 4T1 + 4PYR vs. 4T1 and control. Vascular relaxation caused by flow-dependent endothelial activation in 4PYR-treated mice was significantly lower than in control. The permeability of 4PYR-treated endothelial cells was increased. Decreased nicotinamide but enhanced nicotinamide metabolites were noticed in 4T1 vs. control. Reduced N-methylnicotinamide and a further increase in Met2PY were observed in 4T1 + 4PYR vs. 4T1 and control. In cultured breast cancer cells, estrogen and progesterone receptor antagonists inhibited the production of 4PYR metabolites. 4PYR formation is accelerated in cancer and induces metabolic disturbances that may affect cancer progression and, especially, metastasis, probably through impaired endothelial homeostasis. 4PYR may be considered a new oncometabolite.

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“…This ribosylated pyridone is also found abundantly in circulation in uremic patients. Importantly, it is easily converted to its nucleotide forms (4PYR-MP, 4PYR-DP, 4PYR-TP, [76][77][78][79][80][81][82]. Both the phosphorylated forms of 4PYR and its dinucleotide forms are endogenously generated.…”

Section: The Chemistry Of the Nad(p)(h) Pool The Anabolites And Catabmentioning

confidence: 99%

The chemistry of the vitamin B3 metabolome

Makarov

Trammell

Migaud

2018

Biochemical Society Transactions

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The functional cofactors derived from vitamin B3 are nicotinamide adenine dinucleotide (NAD+), its phosphorylated form, nicotinamide adenine dinucleotide phosphate (NADP+) and their reduced forms (NAD(P)H). These cofactors, together referred as the NAD(P)(H) pool, are intimately implicated in all essential bioenergetics, anabolic and catabolic pathways in all forms of life. This pool also contributes to post-translational protein modifications and second messenger generation. Since NAD+ seats at the cross-road between cell metabolism and cell signaling, manipulation of NAD+ bioavailability through vitamin B3 supplementation has become a valuable nutritional and therapeutic avenue. Yet, much remains unexplored regarding vitamin B3 metabolism. The present review highlights the chemical diversity of the vitamin B3-derived anabolites and catabolites of NAD+ and offers a chemical perspective on the approaches adopted to identify, modulate and measure the contribution of various precursors to the NAD(P)(H) pool.

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Metabolism of 4-Pyridone-3-Carboxamide-1-ß-D- Ribonucleoside Triphosphate and Its Nucleoside Precursor in the Erythrocytes

Cited by 17 publications

References 3 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?

An unusual nicotinamide derivative, 4-pyridone-3-carboxamide ribonucleoside (4PYR), is a novel endothelial toxin and oncometabolite

The chemistry of the vitamin B3 metabolome

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