Palmitoylation-dependent activation of NADK promotes NADP+ synthesis and tumorigenesis

Chen, L.; Zhang, W.; Zhu, Y.; Xing, X.; Yao, Y.; Pei, H.; Chen, Y.; Qin, W.; Zhang, P.

doi:10.1101/2025.07.24.666230

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bioRxiv · 10.1101/2025.07.24.666230

Palmitoylation-dependent activation of NADK promotes NADP+ synthesis and tumorigenesis

Chen, L.·Zhang, W.·Zhu, Y.·Xing, X.·Yao, Y.·Pei, H.·Chen, Y.·Qin, W.·Zhang, P.

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Abstract

NAD kinase (NADK) is the sole cytosolic enzyme that catalyzes the synthesis of nicotinamide adenine dinucleotide phosphate (NADP+) from NAD+. NADP+ is essential for anabolic reactions and redox balance. Here, we show that palmitate facilitates NADP+ synthesis by enhancing NADK palmitoylation and activity. NADK is post-translationally S-palmitoylated on three cysteine residues (Cys22, Cys23, and Cys26) within the amino-terminal domain by the protein-acyl transferase ZDHHC5, which stimulates NADK activity. Fatty acids activate NADK by enhancing its palmitoylation and relief of an autoinhibitory function inherent to its amino terminus. Furthermore, ZDHHC5-/- mice showed defect in NADK palmitoylation and NADP+ production. Clinically, elevated expression of ZDHHC5 in pancreatic cancer patients was associated with increased NADK palmitoylation and correlated with poor prognoses for patients. These data reveal that fatty-acid and ZDHHC5-mediated palmitoylation has a critical role in NADP+ synthesis and cancers.

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Chen, L., Zhang, W., Zhu, Y., Xing, X., Yao, Y., Pei, H., Chen, Y., Qin, W., Zhang, P.. 2025-07-27. Palmitoylation-dependent activation of NADK promotes NADP+ synthesis and tumorigenesis. https://doi.org/10.1101/2025.07.24.666230

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