NAD⁺and Vitamin B₃: From Metabolism to Therapies

Abstract

The role of NAD ϩ metabolism in health and disease is of increased interest as the use of niacin (nicotinic acid) has emerged as a major therapy for treatment of hyperlipidemias and with the recognition that nicotinamide can protect tissues and NAD ϩ metabolism in a variety of disease states, including ischemia/reperfusion. In addition, a growing body of evidence supports the view that NAD ϩ metabolism regulates important biological effects, including lifespan. NAD ϩ exerts potent effects through the poly(ADP-ribose) polymerases, mono-ADPribosyltransferases, and the recently characterized sirtuin enzymes. These enzymes catalyze protein modifications, such as ADP-ribosylation and deacetylation, leading to changes in protein function. These enzymes regulate apoptosis, DNA repair, stress resistance, metabolism, and endocrine signaling, suggesting that these enzymes and/or NAD ϩ metabolism could be targeted for therapeutic benefit. This review considers current knowledge of NAD ϩ metabolism in humans and microbes, including new insights into mechanisms that regulate NAD ϩ biosynthetic pathways, current use of nicotinamide and nicotinic acid as pharmacological agents, and opportunities for drug design that are directed at modulation of NAD ϩ biosynthesis for treatment of human disorders and infections.Vitamin B 3 (nicotinamide and nicotinic acid) is essential to all living cells. Vitamin B 3 is biosynthetically converted to nicotinamide adenine dinucleotide (Fig. 1, NAD ϩ ), a versatile acceptor of hydride equivalents to form the reduced dinucleotide, NADH. The phosphorylated forms of the nicotinamide dinucleotides (NADP/NADPH) perform similar chemical functions within cells, although these are generally used in biosynthetic pathways and in cell protection mechanisms against reactive oxygen species. NAD(P)H provides reducing equivalents for cellular biochemistry and energy metabolism. Within eukaryotic cells, energy metabolism is largely mediated by electron transport chains found within the mitochondrion, and NADH plays a vital role in furnishing reducing equivalents to fuel oxidative phosphorylation. Thus, cellular energy metabolism is substantially mediated by vitamin B 3 -derived cofactors, and a large fraction of anabolic and catabolic pathways incorporates these cofactors within them.Nicotinamide dinucleotides also react as electrophiles to transfer the ADP-ribose (ADPR) moiety to a nucleophile. ADPR transfer to small nucleophiles forms ADPR (nucleophile/water), cyclic-ADPR (nucleophile/N1 adenine), and nicotinic acid adenine dinucleotide-phosphate (derived from NADP ϩ , nucleophile/nicotinic acid). These compounds have been shown to regulate processes, such as channel opening and calcium release (Pollak et al., 2007). Furthermore, ADPR transfer modifies protein nucleophilic side chains (Hassa et al., 2006). The ADPR-transfer enzymes fall into three distinct families, the mono-ADP-ribosyltransferases (Hassa et al., 2006), the poly(ADP-ribosyl) polymerases (PARPs) (Virag and Szabo, 2002;Hassa et al., 200...

Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT), an Enzyme Essential for NAD+ Biosynthesis, Leads to Altered Carbohydrate Metabolism in Cancer Cells

“…In mammals, NAD ϩ can be synthesized from nicotinamide, nicotinic acid, or tryptophan (2)(3)(4)(5). However, the nicotinamide salvage pathway represents the major route to NAD ϩ biosynthesis in mammals (6 -8).…”

Sirtuins as novel players in the pathogenesis of diabetes mellitus

“…Hence, activation of SIRT1 may become a novel target in the treatment of diabetic nephropathy [66] . Niacin (vitamin B3), is also an important intermediate for the biosynthesis of NAD + that can used for the activation of SIRT1 [67] . Metformin, a commonly used anti-diabetic drug, decreases insulin resistance and hyperglycemia by inhibiting gluconeogenesis and hepatic glucose output, and activation of free fatty acid oxidation in skeletal muscle [68] .…”

A Novel Methodology for the Quantification of B-Vitamers in Breast Milk

“…B 9 concentration was obtained by adding folic acid, 5-Me THF and p-ABGA concentrations. Our results show that the main secreted form was found to be folic acid, contributing to about 75% of total vitamin B 9 . The presence of polyglutamate forms was investigated but our findings go against previous findings [46].…”

“…Their adequate level plays a key role in avoiding deficiencies and health risks of humans at all stages of life. Prominent examples include but not limited to are, ariboflavinosis [8], pellagra [9], cardiovascular risk [10], cognitive impairment [11] and neural tube defect [12,13].…”