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

• Published in: Nature (London) 2022-08, Vol.608 (7921), p.192-198
• Main Authors: Dibble, Christian C., Barritt, Samuel A., Perry, Grace E., Lien, Evan C., Geck, Renee C., DuBois-Coyne, Sarah E., Bartee, David, Zengeya, Thomas T., Cohen, Emily B., Yuan, Min, Hopkins, Benjamin D., Meier, Jordan L., Clohessy, John G., Asara, John M., Cantley, Lewis C., Toker, Alex
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13; 38; 42; 42/109; 631/45/320; 631/67/2327; 64; 64/60; 96; 96/106; 96/44; 96/95; AKT protein; Antibodies; Cancer; Coenzyme A; Cofactors; Enzymes; Growth factors; Hormones; Humanities and Social Sciences; Insulin; Kinases; Labeling; Lipid metabolism; Lipids; Mammals; Metabolism; Metabolites; Metabolomics; multidisciplinary; Mutation; Nutrient uptake; Nutrients; Pantothenate kinase; Phosphorylation; PTEN protein; Regulation; Regulatory mechanisms (biology); Science; Science (multidisciplinary); Scientific imaging; Signaling; Spectrometry; Substrates; Tyrosine
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-04984-8

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 biosynthesis 1 . Many of the driver mutations in cancer with the highest recurrence, including in receptor tyrosine kinases, Ras, PTEN and PI3K, pathologically activate PI3K signalling 2 , 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 cells 4 , 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 AKT 8 . Although PANK2 is known to catalyse the rate-determining first step of CoA synthesis, we find that the minimally characterized but highly conserved PANK4 9 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. The PI3K–PANK4 axis regulates coenzyme A synthesis, the abundance of acetyl-CoA, and CoA-dependent processes such as lipid metabolism, and these regulatory mechanisms coordinate cellular CoA supplies with the demands of hormone and growth-factor-driven or oncogene-driven metabolism and growth.