Defining NAD(P)(H) Catabolism

Abstract

Dietary vitamin B3 components, such as nicotinamide and nicotinic acid, are precursors to the ubiquitous redox cofactor nicotinamide adenine dinucleotide (NAD+). NAD+ levels are thought to decline with age and disease. While the drivers of this decline remain under intense investigation, strategies have emerged seeking to functionally maintain NAD+ levels through supplementation with NAD+ biosynthetic intermediates. These include marketed products, such as nicotinamide riboside (NR) and its phosphorylated form (NMN). More recent developments have shown that NRH (the reduced form of NR) and its phosphorylated form NMNH also increases NAD+ levels upon administration, although they initially generate NADH (the reduced form of NAD+). Other means to increase the combined levels of NAD+ and NADH, NAD(H), include the inhibition of NAD+-consuming enzymes or activation of biosynthetic pathways. Multiple studies have shown that supplementation with an NAD(H) precursor changes the profile of NAD(H) catabolism. Yet, the pharmacological significance of NAD(H) catabolites is rarely considered although the distribution and abundance of these catabolites differ depending on the NAD(H) precursor used, the species in which the study is conducted, and the tissues used for the quantification. Significantly, some of these metabolites have emerged as biomarkers in physiological disorders and might not be innocuous. Herein, we review the known and emerging catabolites of the NAD(H) metabolome and highlight their biochemical and physiological function as well as key chemical and biochemical reactions leading to their formation. Furthermore, we emphasize the need for analytical methods that inform on the full NAD(H) metabolome since the relative abundance of NAD(H) catabolites informs how NAD(H) precursors are used, recycled, and eliminated.

Synthesis, Detection, and Metabolism of Pyridone Ribosides, Products of NAD Overoxidation

“…This is particularly noticeable for the PYR and ox-NAD series. This overlap is likely encountered by other research groups reporting on the oxidized forms of nicotinamide, methyl nicotinamide, NR + , and NAD + , thus accounting for the lack of comprehensive description of the individual species in the literature . We are currently developing series-specific separation methods to address this shortcoming of LC-MS detection and quantification.…”

“…Other catabolites of nicotinamide include nicotinamide N -oxide and 6-hydroxynicotinamide, also known as 6-oxopyridine-3-carboxamide (6-PY, Figure ), the nonmethylated form of N -Me-6-PY. Additional NAD + urinary metabolites include the ribosylated forms of these PY nucleobases, the pyridone ribosides (Figure , PYRs). − While less abundant than N -Me-PYs, carboxamide pyridone ribosides (PYRs) have been detected numerous times in mammalian urine since the 1970s . Yet, the metabolomics literature often only reports on the 1-ribosylpyridin-4-one-3-carboxamide (4-PYR; Figure ) species (e.g., ref ).…”

Transcriptome in Liver of Periparturient Dairy Cows Differs between Supplementation of Rumen-Protected Niacin and Rumen-Protected Nicotinamide

“…The role is mainly mediated through the niacin receptor, the G-protein–coupled receptor (GPCR) GPR109A, as well as by non-competitively inhibiting the activity of key rate-limiting enzymes in hepatic triglyceride synthesis [ 9 ]. In addition to its role in lipid metabolism, NA also improves dyslipidemia and reduces inflammation in adipose tissues by affecting key genes involved in gluconeogenesis, which in turn modulate the expression of genes associated with glycolysis, the pentose phosphate pathway, lipid and cholesterol synthesis, lipid transport, and very-low-density lipoprotein (VLDL)/LDL assembly [ 6 , 7 , 8 , 10 , 11 , 12 ]. Excessive accumulation of liver fat leads to elevated levels of reactive oxygen species(ROS) and exacerbates inflammation, while the addition of NA into cultured hepatocytes alleviated lipid accumulation, inhibited ROS production, and reduced the levels of pro-inflammatory factors [ 13 ].Unlike NA, NAM can reduce blood fatty acid content by promoting lipid synthesis, and perinatal supplementation of NAM facilitates the transformation of the rumen fermentation mode to the propionic acid type, which not only improves the efficiency of liver energy metabolism, but also promotes lipid metabolism [ 14 ].…”