《生命科学》 2025, 37(9): 1065-1074

支链α-酮酸脱氢酶激酶(BCKDK)的研究进展

王崇羽^1,2 , 陈少茹^2,* , 李　佳^1,2,3,4,5,*

¹遵义医科大学，遵义 563006 ²中科中山药物创新研究院，中山 528400 ³中国科学院上海 药物研究所，生命过程小分子调控全国重点实验室，上海 201203 ⁴国科大杭州高等研究院，杭 州 310000 ⁵中科环渤海(烟台)药物高等研究院，烟台新药创制山东省实验室，烟台 264117

摘　要：

支链α- 酮酸脱氢酶激酶(branched-chain α-keto acid dehydrogenase kinase, BCKDK) 是支链氨基酸(branched-chain amino acid, BCAA) 代谢的负调控激酶，通过磷酸化支链α- 酮酸脱氢酶复合体(branched-chain  α-keto acid dehydrogenase complex, BCKDH) 的E1α 亚基，下调  BCKDH 活性，抑制BCAA 代谢。近年来，BCKDK 在疾病中的作用备受关注。在代谢性疾病中，BCKDK 活性升高导致BCAA 累积，与肥胖、糖尿病和脂肪肝发病密切相关，抑制其活性可改善代谢紊乱；在神经退行性疾病中，BCKDK 通过调控BCAA代谢影响神经炎症和神经元功能，抑制其活性可展现神经保护潜力；在癌症中，BCKDK 参与肿瘤代谢重编程，成为潜在治疗靶点；在其他疾病中，BCKDK 也扮演着重要角色。本文综述了BCKDK 对代谢的调控和对疾病发病机制的影响，以及作为潜在治疗靶点的药物研发进程。

通讯作者：陈少茹 , Email:chenshaoru272@zidd.ac.cn 李　佳 , Email:jli@simm.ac.cn

Research progress on branched-chain α-keto acid dehydrogenase kinase (BCKDK)

WANG Chong-Yu^1,2 , CHEN Shao-Ru^2,* , LI Jia^1,2,3,4,5,*

¹Zunyi Medical University, Zunyi 563006, China ²Zhongshan Institute for Drug Discovery, Zhongshan 528400, China ³State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China ⁴Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310000, China ⁵Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China

Abstract:

Branched-chain α-keto acid dehydrogenase kinase (BCKDK) is a negative regulatory kinase that modulates the branched-chain amino acid metabolic pathway. It down-regulates the overall activity of the branched-chain α-keto acid dehydrogenase complex (BCKDH) by  phosphorylating the E1α subunit, thereby reducing the catabolism of BCAA. Recently, BCKDK has garnered  significant attention in various diseases. In metabolic disorders diseases, hyperactive BCKDK leads to BCAA   accumulation, which is closely associated with obesity, diabetes, and non-alcoholic fatty liver diseases (NAFLD); then the inhibition of BCKDK activity could improve  metabolic dysregulation. BCKDK could also affect neuron-inflammation and neuronal function by regulating BCAA metabolism in neurodegeneration diseases. It seems that inhibiting BCKDK activity exhibits potential neuroprotective effect. In cancer diseases, BCKDK  involved in tumor metabolic reprogramming, promoting tumor growth, which emerged as a potential therapeutic target. BCKDK also plays important roles in other diseases. This review elucidates the regulatory mechanism of BCKDK in metabolism and the role in diseases pathogenesis as well as the research progress targeting BCKDK as a potential therapeutic strategy.

Communication Author：CHEN Shao-Ru , Email:chenshaoru272@zidd.ac.cn LI Jia , Email:jli@simm.ac.cn