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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 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

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Direct stimulation of NADP <sup>+</sup> synthesis through Akt-mediated phosphorylation of NAD kinase'. Together they form a unique fingerprint.

Cite this