nicotinamide adenine dinucleotide

**Structure and synthesis** - Dinucleotide made of two nucleotides joined by phosphate groups: one contains adenine, the other contains nicotinamide (the active vitamin B3 moiety), each with a ribose. - Derived from niacin (nicotinic acid/nicotinamide) in the diet, and synthesized from tryptophan (requires vitamin B6 for the kynurenine pathway; about 60 mg tryptophan = 1 mg niacin). The ribose and adenine come from PRPP/ATP. - NADP+/NADPH has an extra phosphate on the 2' ribose (added by NAD kinase).

**Function: oxidation vs. reduction roles** - **NAD+ (oxidized form)** is used mainly in **catabolic** pathways. It accepts a hydride ion (H–, 2 e– + 1 H+) from substrates and becomes NADH. Dehydrogenases use it. - **NADH** carries electrons to **Complex I (NADH dehydrogenase)** of the ETC. This yields about 2.5 ATP per NADH, compared with about 1.5 ATP per FADH2, which enters at Complex II. - **NADPH** is used mainly in **anabolic** pathways and for antioxidant defense. See below.

**Key reactions that generate NADH (high-yield)** - Glycolysis: glyceraldehyde-3-phosphate dehydrogenase. - Pyruvate dehydrogenase complex (needs B1, B2, B3, B5, lipoic acid). - TCA cycle: isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase. - β-oxidation of fatty acids. - Ethanol metabolism: alcohol dehydrogenase (ethanol → acetaldehyde) and acetaldehyde dehydrogenase (acetaldehyde → acetate). Both steps use NAD+, so ethanol raises the NADH/NAD+ ratio.

**Clinical significance of an elevated NADH/NAD+ ratio (ethanol metabolism)** - Pyruvate → lactate (lactic acidosis). - Oxaloacetate → malate, which impairs gluconeogenesis and causes fasting hypoglycemia. - Inhibition of fatty acid oxidation and promotion of fatty acid synthesis lead to hepatic steatosis. - Glycerol-3-phosphate and DHAP shift toward triglyceride synthesis.

**Related NADPH points (often tested alongside NAD)** - Produced by the HMP shunt (G6PD) and malic enzyme. - Used for fatty acid and steroid synthesis, glutathione reduction, the respiratory burst (NADPH oxidase), and cytochrome P-450. - Defects: G6PD deficiency (hemolysis, Heinz bodies, bite cells) and chronic granulomatous disease (NADPH oxidase defect).

**Niacin (B3) deficiency and excess** - **Pellagra**: the 3 D's (**D**ermatitis in sun-exposed areas, such as Casal necklace, plus **D**iarrhea and **D**ementia), and in severe cases death (4th D). - Causes: poor diet (corn-based diets where niacin is unavailable unless treated with alkali), **Hartnup disease** (defective neutral amino acid/tryptophan absorption), **carcinoid syndrome** (tryptophan diverted to serotonin), **isoniazid** (B6 deficiency), and malabsorption. - Niacin therapy for dyslipidemia: lowers LDL and TG and raises HDL the most (inhibits lipolysis in adipose tissue). Adverse effects: cutaneous flushing (prostaglandin-mediated, reduced with aspirin or laropiprant), hyperglycemia, hyperuricemia (gout), and hepatotoxicity.

**Other roles of NAD+** - Substrate for **sirtuins** (deacetylases), **PARP** (poly-ADP-ribose polymerase, DNA repair), and ADP-ribosylation toxins. Cholera toxin, pertussis toxin, and diphtheria toxin use NAD+ as the ADP-ribose donor. Diphtheria toxin ADP-ribosylates EF-2, which inhibits protein synthesis. - Lactate dehydrogenase uses NAD+/NADH to interconvert lactate and pyruvate. Anaerobic glycolysis depends on regenerating NAD+ via lactate formation. - Malate-aspartate and glycerol-3-phosphate shuttles move cytosolic NADH reducing equivalents into mitochondria. The malate-aspartate shuttle (liver, heart) gives NADH, while the glycerol-3-phosphate shuttle (muscle) gives FADH2.

**Mnemonic**: NAD+ = **N**eeded for **A**ctual **D**egradation (catabolism). NADPH = **P**roduction (anabolism).