NAD+ metabolism (WP3644)

NAD+ metabolism in different cellular compartments. The different precursors to intracellular NAD metabolism - tryptophan, nicotinic acid (NA), nicotinamide, NR, and NMN - are shown, along with their extra-cellular metabolism by CD38 and CD73. The cytoplasmic and nuclear NAD+ pools probably equilibrate by diffusion through the nuclear pore. However, the mitochondrial membrane is impermeable to both NAD+ and NADH. Reducing equivalents generated by glycolysis are transferred to the mitochondrial matrix via the malate/aspartate shuttle and the glyceraldehyde-3-phosphate shuttle. The resulting mitochondrial NADH (malate/aspartate shuttle) is oxidized by complex I in the electron transport chain, whereas the resulting FADH2 (glyceraldehyde-3-phosphate shuttle) is oxidized by complex II. In each of the three compartments, different NAD+-consuming enzymes lead to the generation of nicotinamide, which is recycled via the NAD+ salvage pathway. Different forms of the NMNAT enzyme and sirtuins are localized in different compartments. The nature of the salvage pathway for NAD+ in mitochondria has not been fully resolved, although NMNAT3 has been found in mitochondria. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP3644 CPTAC Assay Portal]

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