小柯机器人

美国哈佛医学院Alex Toker、Christian C. Dibble等研究人员合作发现，PI3K驱动从维生素B5中从头合成辅酶A。该研究于2022年7月27日在线发表于国际一流学术期刊《自然》。

利用基于质谱的代谢组学和同位素追踪，研究人员发现，磷脂酰肌醇-3-激酶（PI3K）信号刺激了最关键的代谢辅助因子之一的从头合成：辅酶A（CoA）。辅酶A是细胞中活性酰基的主要载体，由半胱氨酸、ATP和基本营养素维生素B5（也称为泛酸）合成。研究人员确定泛酸激酶2（PANK2）和PANK4是PI3K效应激酶AKT8的底物。虽然已知PANK2催化CoA合成的决定性第一步，但研究人员发现表征最少但高度保守的PANK4通过其代谢物磷酸酶活性作为CoA合成的一个限速抑制因子。AKT对PANK4的磷酸化可以解除这种抑制作用。最终，PI3K-PANK4轴调节乙酰CoA和其他酰基CoA的丰度、CoA依赖过程，如脂质代谢和增殖。研究人员提出，这些调节机制协调了细胞CoA供应与激素/生长因子驱动或肿瘤基因驱动的代谢和生长的需求。

据悉，在对激素和生长因子的反应中，第一类PI3K信号网络作为代谢和生长的主要调节器发挥作用，管理细胞的营养吸收、能量生成、减少辅助因子的产生和大分子生物合成。复发率最高的癌症中的许多驱动突变，包括受体酪氨酸激酶、Ras、PTEN和PI3K中的驱动突变，都从病理上激活PI3K信号。然而，人们对PI3K所控制的核心代谢程序的理解几乎肯定是不完整的。

附：英文原文

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

Author: 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

Issue&Volume: 2022-07-27

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.

DOI: 10.1038/s41586-022-04984-8

Source: https://www.nature.com/articles/s41586-022-04984-8

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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