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

Gerta Hoxhaj, Issam Ben-Sahra, Sophie E. Lockwood, Rebecca C. Timson, Vanessa Byles, Graham T. Henning, Peng Gao, Laura M. Selfors, John M. Asara, Brendan D. Manning

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10 Scopus citations

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 (Ser 44 , Ser 46 , and Ser 48 ) 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.

Original languageEnglish (US)
Pages (from-to)1088-1092
Number of pages5
JournalScience
Volume363
Issue number6431
DOIs
StatePublished - 2019
Externally publishedYes

ASJC Scopus subject areas

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    Hoxhaj, G., Ben-Sahra, I., Lockwood, S. E., Timson, R. C., Byles, V., Henning, G. T., Gao, P., Selfors, L. M., Asara, J. M., & Manning, B. D. (2019). Direct stimulation of NADP + synthesis through Akt-mediated phosphorylation of NAD kinase Science, 363(6431), 1088-1092. https://doi.org/10.1126/science.aau3903