PI3K–AKT Inhibits PANK4 to Promote De Novo Synthesis of Coenzyme A

Frequently mutated and hyperactivated in human tumors, the PI3K–AKT signaling axis controls many pathways that coordinately promote cancer proliferation, survival, and metabolism. To identify the core metabolic program driven by PI3K, Dibble, Barritt, and colleagues performed a targeted metabolomic analysis in nontransformed human breast epithelial cells stimulated with insulin in the presence or absence of a PI3K inhibitor. PI3K signaling through the effector kinase AKT increased levels of the key metabolic cofactor coenzyme A (CoA) that had been newly synthesized from vitamin B5 (also known as pantothenate), while PI3K inhibition decreased newly synthesized CoA levels while increasing vitamin B5 levels, suggesting that PI3K–AKT promotes vitamin B5 metabolism for the de novo synthesis of CoA. Sequence analysis of CoA synthesis enzymes revealed AKT substrate consensus motifs within the pantothenate kinase family members PANK2 and PANK4, which were confirmed as AKT substrates via endogenous immunoprecipitation analyses. Whereas PANK2 is known to phosphorylate vitamin B5 in the first rate-limiting step of CoA synthesis, PANK4 contains a catalytically inactive kinase domain and its function is not well understood. Notably, genetic depletion of PANK4 enhanced AKT-mediated CoA synthesis, demonstrating a novel regulatory role for PANK4. Reconstitution of phosphorylation-deficient PANK4 (T406A) in PANK4-knockout cells enhanced suppression of CoA synthesis compared with wild-type PANK4, suggesting that AKT-mediated phosphorylation of PANK4 attenuates its inhibitory effect on CoA synthesis. PANK4 contains a minimally characterized, putative DUF89 phosphatase domain and was shown to suppress CoA synthesis through its phosphatase activity for the third CoA synthesis intermediate, 4′-phosphopantetheine. PANK4-mediated reduction of CoA synthesis impaired CoA-dependent fatty acid synthesis, lipid assembly, mitochondrial respiration, and histone acetylation, highlighting the diverse metabolic consequences of changes in CoA metabolism. Moreover, PANK4 phosphatase activity suppressed proliferation and colony formation in vitro while reducing tumor growth in vivo. In summary, this work describes a mechanism in which PI3K–AKT signaling inhibits the function of a regulatory enzyme to promote CoA synthesis, delineating a novel, protumorigenic pathway of AKT-mediated metabolic control.

Dibble CC, Barritt SA, Perry GE, Lien EC, Geck RC, Dubois-Coyne SE, et al. PI3K drives the de novo synthesis of coenzyme A from vitamin B5. Nature 2022;608:192–8.

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