ArticleProceedings of the National Academy of Sciences of the United States of America2013
Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain α-ketoacid dehydrogenase kinase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
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Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it, 71 citations in OpenAlex.
- Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis.PLoS medicine · 2016Pooled it
- Off-target depletion of plasma tryptophan by allosteric inhibitors of BCKDK.Molecular metabolism · 2025Article
- Branched-Chain Amino Acid Metabolic Reprogramming and Cancer: Molecular Mechanisms, Immune Regulation, and Precision Targeting.Oncology research · 2025Review
- Anaplerotic filling in heart failure: a review of mechanism and potential therapeutics.Cardiovascular research · 2024Review
- Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation.Journal of enzyme inhibition and medicinal chemistry · 2024Article
- Bicyclic Inhibitors of Branched-Chain α-Keto Acid Dehydrogenase Kinase (BDK) with In Vivo Activity.ACS medicinal chemistry letters · 2024Article
- Computational structural genomics and clinical evidence suggest BCKDK gain-of-function may cause a potentially asymptomatic maple syrup urine disease phenotype.JIMD reports · 2024Article
- Mitochondrial Alpha-Keto Acid Dehydrogenase Complexes: Recent Developments on Structure and Function in Health and Disease.Sub-cellular biochemistry · 2024Review
- Targeting BCAA metabolism to potentiate metformin's therapeutic efficacy in the treatment of diabetes in mice.Diabetologia · 2023Article
- Depiction of Branched-Chain Amino Acids (BCAAs) in Diabetes with a Focus on Diabetic Microvascular Complications.Journal of clinical medicine · 2023Review
- Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels.Nature communications · 2023Article
- Combining structural and coevolution information to unveil allosteric sites.Chemical science · 2023Article
- Branched-Chain Amino Acids Metabolism and Their Roles in Retinopathy: From Relevance to Mechanism.Nutrients · 2023Review
- Attenuated glucose uptake promotes catabolic metabolism through activated AMPK signaling and impaired insulin signaling in zebrafish.Frontiers in nutrition · 2023Article
- Role of branched-chain amino acid metabolism in the pathogenesis of obesity and type 2 diabetes-related metabolic disturbances BCAA metabolism in type 2 diabetes.Nutrition & diabetes · 2022Review
- Urine and FecalMetabolites · 2022Article
- A Gain-of-Function Mutation onGenes · 2022Article
- Evaluation of therapeutic strategies targeting BCAA catabolism using a systems pharmacology model.Frontiers in pharmacology · 2022Article
- The Role of Branched-Chain Amino Acids and Branched-Chain α-Keto Acid Dehydrogenase Kinase in Metabolic Disorders.Frontiers in nutrition · 2022Review
- Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street.Molecular metabolism · 2021Review
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 1 country.
Funding
Abstract
The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are elevated in maple syrup urine disease, heart failure, obesity, and type 2 diabetes. BCAA homeostasis is controlled by the mitochondrial branched-chain α-ketoacid dehydrogenase complex (BCKDC), which is negatively regulated by the specific BCKD kinase (BDK). Here, we used structure-based design to develop a BDK inhibitor, (S)-α-chloro-phenylpropionic acid [(S)-CPP]. Crystal structures of the BDK-(S)-CPP complex show that (S)-CPP binds to a unique allosteric site in the N-terminal domain, triggering helix movements in BDK. These conformational changes are communicated to the lipoyl-binding pocket, which nullifies BDK activity by blocking its binding to the BCKDC core. Administration of (S)-CPP to mice leads to the full activation and dephosphorylation of BCKDC with significant reduction in plasma BCAA concentrations. The results buttress the concept of targeting mitochondrial BDK as a pharmacological approach to mitigate BCAA accumulation in metabolic diseases and heart failure.
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Registered trials
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