NAD(+) metabolism: Bioenergetics, signaling and manipulation for therapy

Abstract

We survey the historical development of scientific knowledge surrounding Vitamin B3, and describe the active metabolite forms of Vitamin B3, the pyridine dinucleotides NAD⁺ and NADP⁺ which are essential to cellular processes of energy metabolism, cell protection and biosynthesis. The study of NAD⁺ has become reinvigorated by new understandings that dynamics within NAD⁺ metabolism trigger major signaling processes coupled to effectors (sirtuins, PARPs, and CD38) that reprogram cellular metabolism using NAD⁺ as an effector substrate. Cellular adaptations include stimulation of mitochondrial biogenesis, a process fundamental to adjusting cellular and tissue physiology to reduced nutrient availability and/or increased energy demand. Several mammalian metabolic pathways converge to NAD⁺, including tryptophan-derived de novo pathways, nicotinamide salvage pathways, nicotinic acid salvage and nucleoside salvage pathways incorporating nicotinamide riboside and nicotinic acid riboside. Key discoveries highlight a therapeutic potential for targeting NAD⁺ biosynthetic pathways for treatment of human diseases. A recent emergence of understanding that NAD⁺ homeostasis is vulnerable to aging and disease processes has stimulated testing to determine if replenishment or augmentation of cellular or tissue NAD⁺ can have ameliorative effects on aging or disease phenotypes. This experimental approach has provided several proofs of concept successes demonstrating that replenishment or augmentation of NAD⁺ concentrations can provide ameliorative or curative benefits. Thus NAD⁺ metabolic pathways can provide key biomarkers and parameters for assessing and modulating organism health.

Keywords: NADH; Nicotinamide adenine dinucleotide; Nicotinamide riboside; Nicotinic acid riboside; Tryptophan; Vitamin B3.

Figure 1. Integration of NAD⁺ and NADH into cellular energy metabolism

NAD⁺ reduction to NADH is featured in glycolysis, pyruvate dehydrogenase, and the tricarboxylic acid cycle (TCA cycle). NADH oxidation to NAD⁺ occurs in the cytoplasm by action of lactate dehydrogenase and in mitochondria by action of Complex I. These oxidations maintain the high NAD⁺/NADH ratio maintained by mammalian cells and the majority of mitochondrial production of ATP is directly linked to Complex I activity. Abbreviations: glucose 6-phosphate, G6P; fructose-6-phosphate, F6P; fructose-1,6-bisphosphate, F1,6BP; glyceraldehyde-3-phosphate; 3-phosphoglycerate, 3PG; phosphoenol pyruvate; oxaloacetate, OA; citrate, CIT; cis-aconitate, cisACT; isocitrate, isoCIT; alpha-ketoglutarate, αKG; succinylCoA, SUCCoA; succinate, SUC; fumarate, FUM; malonate, MAL. Coenzyme Q, CoQ.

Figure 2. Tryptophan-Derived Biosynthesis of NAD⁺ via Kynurenine Pathway

Enzymes are A) tryptophan 2,3-dioxygenase B) kynurenine mono-oxygenase C) kynureninase D) 3-hydroxyanthranilate 3,4,-dioxygenase E) no-enzyme F) Quinolinate phosphoribosyltransferase G) nicotinic acid/nicotinamide mononucleotide adenylyltransferase (Nmnat 1, 2, 3) H) NAD synthetase. I) 2-amino-3-carboxy-muconate-semialdehyde decarboxylase (ACMSD) which acts upon 2-amino-3-carboxy-muconate-semialdehyde to form picolinic acid, as an alternative pathway fed by the kynurenine catabolic pathway, as discussed in the text.

Figure 3. Nicotinic Acid Salvage Pathway (Preiss-Handler Pathway)

Enzymes are A) nicotinate phosphoribosyltransferase B) nicotinic acid/nicotinamide mononucleotide adenylyltransferase (Nmnat 1, 2, 3) C) NAD⁺ synthetase.

Figure 4. Nicotinamide Core Recycling Pathway

Enzymes are A) nicotinamide phosphoribosyltransferase B) nicotinic acid/nicotinamide mononucleotide adenylyltransferase (Nmnat 1, 2, 3). NAD⁺ is constantly consumed in cells by action of NAD⁺ consumers, including sirtuins, PARP enzymes, CD38 etc., creating a constant supply of nicotinamide, which must be recycled to maintain NAD⁺ homeostasis. The importance and efficiency of this process is discussed in the text.

Figure 5. Nucleoside Salvage Pathway

Enzymes are A) nicotinamide riboside kinase 1 and nicotinamide riboside kinase 2 (Nrk1, Nrk2) B) purine nucleoside phosphorylase C) nicotinic acid phosphoribosyltransferase D) nicotinic acid/nicotinamide mononucleotide adenylyltransferase (Nmnat 1, 2, 3) E) NAD⁺ synthetase F) nicotinamide phosphoribosyltransferase.

Figure 6. Intracellular Import of NAD Precursors and Intracellular Conversions to NAD⁺

Depiction of how different NAD precursors are transported into cells via identified or putative transport systems in cell membranes (embedded cylindrical domains). As can be visualized by the figure, networks of biosynthetic pathways converge to two main NAD biosynthetic intermediates, namely NaMN and NMN. NAD itself provides an action point for several other downstream processes, including biosynthesis of NADP/NADPH and for signaling processes, which regenerates nicotinamide for the core nicotinamide recycling pathway.