Direct stimulation of NADP synthesis through Akt-mediated phosphorylation of NAD kinase.

Nicotinamide adenine dinucleotide phosphate (NADP) is essential for producing NADPH, the primary cofactor for reductive metabolism. We find that growth factor signaling through the phosphoinositide 3-kinase (PI3K)-Akt pathway induces acute synthesis of NADP and NADPH. Akt phosphorylates NAD kinase (NADK), the sole cytosolic enzyme that catalyzes the synthesis of NADP from NAD (the oxidized form of NADH), on three serine residues (Ser, Ser, and Ser) within an amino-terminal domain. This phosphorylation stimulates NADK activity both in cells and directly in vitro, thereby increasing NADP production. A rare isoform of NADK (isoform 3) lacking this regulatory region exhibits constitutively increased activity. These data indicate that Akt-mediated phosphorylation of NADK stimulates its activity to increase NADP production through relief of an autoinhibitory function inherent to its amino terminus.