NAD+ Metabolism
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What is NAD+ composed of?
2 nucleotides linked together by their phosphate groups
What are the 2 nucleotides of NAD+?
• adenine nucleotide – contains adenine as its nitrogenous base (also called AMP) • nicotinamide nucleotide (NMN) – contains nicotinamide as its nitrogenous base
What is adenine?
a purine base
What is nicotinamide (NMN)?
a nitrogenous base and derivative of vitamin B3 (niacin) that gives NAD+ its redox properties
What does the structure of NAD+ allow it to do?
act as a critical electron carrier
What is oxidation and reduction respectively?
• oxidation = loss of electrons (NAD+) • reduction = gain of electrons (NADH)
What happens to NAD+ during redox reactions?
it can accept 2 electrons and 1 proton to become NADH
What is the extracellular concentration of NAD+ in the blood serum of mammals?
between 0.1 and 0.5 µM under physiological conditions
Describe the distribution of NAD+ in cells
• mitochondria - high conc due to energy production • cytosol - lower conc than mitochondria (200-300) involved in glycolysis and other metabolic pathways • nucleus - lower conc than cytosol (100-200) crucial for DNA repair and gene reg • ER - lowest conc used in regulation of protein folding and quality control
What is the half-life of NAD+?
1-2 hours
What is maintaining NAD+ half-life crucial for?
cellular metabolism, DNA repair and longevity
What are the 3 main pathways cells use to produce NAD+?
• Preiss-Handler pathway from niacin • de novo pathway from tryptophan • salvage pathway from recycling NMN
How can NAD+ synthesis be enhanced?
• supplementation with precursors like nicotinamide riboside (NR) or NMN • diet rich in NAD+ precursors • activation of NAMPT enzyme, which recycles nicotinamide into NAD+
What are the 3 main NAD+ consumption enzymes?
• PARPs - activated during DNA repair • CD38 - involved in immune signalling and inflammation • sirtuins - involved in longevity and metabolism
How can excessive NAD+ depletion be minimised?
• reduce chronic inflammation by inhibiting CD38 with apigenin or quercetin • lower oxidative stress by antioxidant-rich diet or exercise • enhance DNA repair efficiency by limiting excessive PARP activation
How does calorie restriction affect NAD+?
it activates the NAMPT enzyme which enhances NAD+ regeneration through salvage pathway
What are the 4 main ways to maintain NAD+ half-life in cells?
• increase NAD+ synthesis (diet, supplementation) • minimise excessive NAD+ consumption (inflammation control, reduce oxidative stress) • enhance NAD+ recycling (exercise, fasting) • support mitochondrial health (nutrition, physical activity)
What are the 4 main precursors to NAD+?
• tryptophan • nicotinic acid (NA) • nicotinamide (NAM) • nicotinamide riboside (NR)
What do NMNATs do?
work in Preiss-Handler and salvage pathway to add an AMP group either to NAMN or NAM, respectively
What is the rate limiting enzyme in the Preiss-Handler pathway?
NAPRT (uses NA as substrate)
What is the rate limiting enzyme in the salvage pathway?
NAMPT (regenerates NMN from NAM)
How is NMN generated?
NR kinase phosphorylates NR
What does the tryptophan degradation pathway lead to?
quinolinic acid as precursor which merges with the Preiss-Handler pathway to make NAD+ (less effective)
What does inhibition of NAMPT in the salvage pathway lead to?
to a loss of NAD+