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Science. 2019 Mar 8;363(6431):1088-1092. doi: 10.1126/science.aau3903.

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

Author information

1
Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
2
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
3
Metabolomics Core Facility, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.
4
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
5
Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, MA, USA.
6
Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA. bmanning@hsph.harvard.edu.

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.

PMID:
30846598
DOI:
10.1126/science.aau3903

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