PI3K drives the de novo synthesis of coenzyme A from vitamin B5

Christian C. Dibble, Samuel A. Barritt, Grace E. Perry, Evan C. Lien, Renee C. Geck, Sarah E. DuBois-Coyne, David Bartee, Thomas T. Zengeya, Emily B. Cohen, Min Yuan, Benjamin D. Hopkins, Jordan L. Meier, John G. Clohessy, John M. Asara, Lewis C. Cantley, Alex Toker

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

In response to hormones and growth factors, the class I phosphoinositide-3-kinase (PI3K) signalling network functions as a major regulator of metabolism and growth, governing cellular nutrient uptake, energy generation, reducing cofactor production and macromolecule biosynthesis1. Many of the driver mutations in cancer with the highest recurrence, including in receptor tyrosine kinases, Ras, PTEN and PI3K, pathologically activate PI3K signalling2,3. However, our understanding of the core metabolic program controlled by PI3K is almost certainly incomplete. Here, using mass-spectrometry-based metabolomics and isotope tracing, we show that PI3K signalling stimulates the de novo synthesis of one of the most pivotal metabolic cofactors: coenzyme A (CoA). CoA is the major carrier of activated acyl groups in cells4,5 and is synthesized from cysteine, ATP and the essential nutrient vitamin B5 (also known as pantothenate)6,7. We identify pantothenate kinase 2 (PANK2) and PANK4 as substrates of the PI3K effector kinase AKT8. Although PANK2 is known to catalyse the rate-determining first step of CoA synthesis, we find that the minimally characterized but highly conserved PANK49 is a rate-limiting suppressor of CoA synthesis through its metabolite phosphatase activity. Phosphorylation of PANK4 by AKT relieves this suppression. Ultimately, the PI3K–PANK4 axis regulates the abundance of acetyl-CoA and other acyl-CoAs, CoA-dependent processes such as lipid metabolism and proliferation. We propose that these regulatory mechanisms coordinate cellular CoA supplies with the demands of hormone/growth-factor-driven or oncogene-driven metabolism and growth.

Original languageEnglish
Pages (from-to)192-198
Number of pages7
JournalNature
Volume608
Issue number7921
DOIs
StatePublished - 4 Aug 2022

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