# Defining NAD(P)(H) catabolism
## 4 Ribosylated Catabolites of NAD(P)(H)
Increased concentrations of 4-PYR was found in the urinary excretions of several pathological conditions such as chronic renal failure [128], breast cancer [129], and chronic myelogenous leukemia patients [130] and was associated with tryptophan metabolism [116]. In patients with chronic renal failure, 4-PYR can accumulate substantially (>50 fold) [97]. [PERSON] and [PERSON] described the distribution of purine nucleotides in uremic fluids and tissues [131; 132] and several studies have provided further insight into the abundance, role, and function of the PYR family. Detailed investigations on this metabolite unveiled the fact that it becomes phosphorylated to its phosphate derivatives (Figure 6) such as 4-pyridone-3-carboxamide-1-\(\beta\)-D-ribonucleoside monophosphate (4-PYR-MP) and 4-pyridone-3-carboxamide-1-\(\beta\)-D-ribonucleoside triphosphate (4-PYR-TP) [115; 117; 131]. Multiple laboratories observed that in erythrocytes, extracellular 4-PYR was the precursor to intracellular 4-PYR-TP via 4-PYR-MP and adenosine kinase [117; 118], although they observed a preferential accumulation of 4-PYR-MP over 4-PYR-TP during the incubation of 4-PYR. Later, [PERSON] et al., observed that other tissues were able to metabolize, circulating 4-PYR to PYR-TP. They demonstrated that just like erythrocytes, other tissues could process 4-PYR including the liver, heart, kidneys, lungs, and skeletal muscles [113]. In addition, they showed that 4-PYR accumulated as 4-PYR-MP in all these tissues except the kidneys. Figure 6: The 4-isomeric form of ribosylated pyridones, catabolites from nicotinamide riboside, nicotinamide mononucleotides, and NAD\({}^{+}\). Measurements of 4-PYR-MP and 4-PYR-TP in human biospecimens revealed that 4-PYR-MP, and 4-PYR-TP are low in healthy adults but become elevated in the patients with chronic renal failure, which links the toxicity of these metabolites to renal anemia [132]. Furthermore, plasma concentration of 4-PYR in patients with chronic renal failure was found to be very high compared with that of healthy subjects. Initially, it was hypothesized that 4-PYR was either rapidly removed from circulation by renal clearance or converted to 4-PYR-TP at a faster rate in healthy subjects to clear this toxic metabolite from the plasma. The need for an effective renal clearance of 4-PYR would point to its possible toxicity and pathological conditions that might result from its accumulation. It was then proposed that prominent 4-PYR accumulation in circulation and peripheral tissues might further impair renal function. To further investigate the effects of 4-PYR metabolites on the various metabolic processes that consume ATP or NAD, the effects of 4-PYR and its phosphorylated derivative 4-PYR-MP were evaluated against the enzymes involved in nucleotide metabolism and cellular metabolism [131; 133; 134]. While 4-PYR showed significant activation of S-adenosylhomocysteine hydrolase (SAHH), 4-PYR-MP was a potent inhibitor of adenosine monophosphate deaminase (AMPD) in erythrocyte lysate (IC\({}_{50}\): 74 uM) and heart homogenates (IC\({}_{50}\): 55 uM). Furthermore, the intracellular production of 4-PYR-MP from 4-PYR led to the inhibition of the AMP deamination pathway. It has been proposed that this inhibition contributes to the accumulation of adenine nucleotide observed in the erythrocytes of patients with chronic renal failure. Using a widely studied animal model of atherosclerosis that shares many similarities to human pathology, [PERSON] et al. observed that mice exposed to 4-PYR exhibited an increased deposition of lipids in their aortas as indicated by an increased area of atherosclerotic plaques in the abdominal region [126; 135]. Furthermore, circulating 4-PYR accelerated atherosclerosis in these mice [136]. Extracellular adenosine deaminase activity was also enhanced upon 4-PYR treatment, decreasing intravascular adenosine levels.