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

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Science  08 Mar 2019:
Vol. 363, Issue 6431, pp. 1088-1092
DOI: 10.1126/science.aau3903

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Akt produces reducing power

The protein kinase Akt provides a link from growth factors to the production of metabolic reducing power within the cell. Hoxhaj et al. discovered that Akt directly phosphorylates nicotinamide adenine dinucleotide kinase (NADK). Catalytic activity of NADK is normally inhibited by its own amino-terminal domain, and phosphorylation by Akt relieved this inhibition. Active NADK produces nicotinamide adenine dinucleotide phosphate (NADP+). NADP+ in turn is required to produce the reduced form of NADP+ (NADPH), which is the primary cofactor for reductive metabolism in the cell.

Science, this issue p. 1088

Abstract

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 (Ser44, Ser46, and Ser48) 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.

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