新兴证据表明，一些代谢酶除了作为可溶性代谢物的磷酸化酶外，也能作为蛋白激酶磷酸化各种蛋白底物，以调节细胞周期、细胞凋亡等许多基本细胞过程。但是，代谢酶是否具有蛋白酸化酶降磷酸化蛋白的功能仍未知。我们在此通过代谢磷酸酶的分子对接高通量筛选和分子动力学模拟，揭示了能将果糖 1,6-双磷酸（F-1,6-BP）水解成果糖 6-磷酸（F-6-P）的糖异生酶果糖 1,6-双磷酸酶 1（FBP1）作为蛋白质磷酸酶的功能。此外，我们通过磷酸蛋白质组学分析，确定了IκBα是FBP1介导的降磷酸化底物。机理上，FBP1在TNFα刺激下直接与IκBα相互作用，并降磷酸化IκBα的丝氨酸32/36位点，从而抑制NF-κB的活化。分子动力学模拟显示，FBP1介导的IκBα降磷酸化催化机制类似于F-1,6-BP的降磷酸化，但是IκBα降磷酸化的能量壁垒更高。从功能上看，FBP1介导的NF-κB失活通过增敏肿瘤细胞对炎症应激的反应并防止髓系抑制细胞的动员，来抑制结直肠肿瘤发生。我们的发现揭示了FBP1作为蛋白酸磷酸酶的一个以前未被发现的作用，以及FBP1介导的IκBα降磷酸化在结直肠肿瘤发生中的关键作用。© 2023。作者（们）独家授权于中科院分子细胞科学卓越中心。

Emerging evidence demonstrates that some metabolic enzymes that phosphorylate soluble metabolites can also phosphorylate a variety of protein substrates as protein kinases to regulate cell cycle, apoptosis and many other fundamental cellular processes. However, whether a metabolic enzyme dephosphorylates protein as a protein phosphatase remains unknown. Here we reveal the gluconeogenic enzyme fructose 1,6-biphosphatase 1 (FBP1) that catalyzes the hydrolysis of fructose 1,6-bisphosphate (F-1,6-BP) to fructose 6-phosphate (F-6-P) as a protein phosphatase by performing a high-throughput screening of metabolic phosphatases with molecular docking followed by molecular dynamics (MD) simulations. Moreover, we identify IκBα as the substrate of FBP1-mediated dephosphorylation by performing phosphoproteomic analysis. Mechanistically, FBP1 directly interacts with and dephosphorylates the serine (S) 32/36 of IκBα upon TNFα stimulation, thereby inhibiting NF-κB activation. MD simulations indicate that the catalytic mechanism of FBP1-mediated IκBα dephosphorylation is similar to F-1,6-BP dephosphorylation, except for higher energetic barriers for IκBα dephosphorylation. Functionally, FBP1-dependent NF-κB inactivation suppresses colorectal tumorigenesis by sensitizing tumor cells to inflammatory stresses and preventing the mobilization of myeloid-derived suppressor cells. Our finding reveals a previously unrecognized role of FBP1 as a protein phosphatase and establishes the critical role of FBP1-mediated IκBα dephosphorylation in colorectal tumorigenesis.© 2023. The Author(s) under exclusive licence to Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences.