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 and Alex Toker ()
Additional contact information
Christian C. Dibble: Harvard Medical School
Samuel A. Barritt: Harvard Medical School
Grace E. Perry: Harvard Medical School
Evan C. Lien: Harvard Medical School
Renee C. Geck: Harvard Medical School
Sarah E. DuBois-Coyne: Harvard Medical School
David Bartee: National Cancer Institute
Thomas T. Zengeya: National Cancer Institute
Emily B. Cohen: Harvard Medical School
Min Yuan: Harvard Medical School
Benjamin D. Hopkins: Icahn School of Medicine at Mount Sinai
Jordan L. Meier: National Cancer Institute
John G. Clohessy: Beth Israel Deaconess Medical Center
John M. Asara: Harvard Medical School
Lewis C. Cantley: Weill Medical College of Cornell University
Alex Toker: Harvard Medical School

Nature, 2022, vol. 608, issue 7921, 192-198

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04984-8

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