Gupta Anshu, Shinde Prasad Govind, Jorvekar Sachin, Humane Akash Suresh, Chandrasekaran Mythri, Borkar Roshan M, Selvaraju Sudhagar
Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Guwahati, India.
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Guwahati, India.
FEBS Lett. 2025 Mar;599(6):892-900. doi: 10.1002/1873-3468.70030. Epub 2025 Mar 6.
Branched-chain amino acids (BCAA) are essential requirements for overall protein turnover, signalling and energy balance, and dysregulation of their metabolic pathway has been associated with many pathophysiological events. Despite the importance of BCAA in human health, our understanding of their metabolic regulation is limited. Here, we present evidence that G protein-coupled oestrogen receptor (GPER) activation inhibits the key BCAA metabolic regulatory enzyme branched-chain α-keto acid dehydrogenase complex (BCKDH) by phosphorylating S293. Inhibition of BCKDH results in leucine, isoleucine and valine accumulation in cells. Interestingly, GPER did not alter the levels of the kinase BCKDK and the phosphatase PPM1K, which regulate BCKDH activity, but activated MAPK signalling. Using gene silencing, we identified that JNK intercedes GPER-mediated BCKDH inhibition. Together, our results demonstrate that GPER inhibits BCAA metabolism through JNK signalling.
支链氨基酸（BCAA）是整体蛋白质周转、信号传导和能量平衡的必需物质，其代谢途径的失调与许多病理生理事件有关。尽管BCAA对人类健康很重要，但我们对其代谢调节的了解有限。在此，我们提供证据表明，G蛋白偶联雌激素受体（GPER）激活通过磷酸化S293抑制关键的BCAA代谢调节酶支链α-酮酸脱氢酶复合体（BCKDH）。BCKDH的抑制导致细胞中亮氨酸、异亮氨酸和缬氨酸的积累。有趣的是，GPER并未改变调节BCKDH活性的激酶BCKDK和磷酸酶PPM1K的水平，但激活了MAPK信号传导。通过基因沉默，我们确定JNK介导了GPER对BCKDH的抑制作用。总之，我们的结果表明，GPER通过JNK信号传导抑制BCAA代谢。
