DeCure for Branched-chain keto acid dehydrogenase kinase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for branched-chain keto acid dehydrogenase kinase deficiency — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleBranched-chain keto acid dehydrogenase kinase deficiency maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for branched-chain keto acid dehydrogenase kinase deficiency is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
What the evidence adds up to
The branched-chain alpha-ketoacid dehydrogenase kinase (BCKDK) inactivates the branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) by phosphorylation, and this kinase activity is the primary regulator of the complex. Nutritional states such as low-protein diet, starvation, diabetes, and exercise affect kinase activity and expression, as do hormones including insulin, glucocorticoid, thyroid hormone and female sex hormones. The kinase thus controls whether branched-chain amino acids are conserved for protein synthesis or catabolised for gluconeogenesis.
A 2001 study determined the three-dimensional structure of rat BCKDK, showing a nucleotide-binding domain and a four-helix bundle domain. ATP binding induces structural changes that trap ADP, explaining product inhibition in mitochondrial protein kinases. The authors stated the structure would provide a framework for structure-assisted inhibitor design for this family of kinases. A 2009 study found that thiamine pyrophosphate inhibits BCKDK with IC50 values of 4.6 and 8.0 microM at 20 and 100 mM potassium, respectively, but concluded the kinase is less sensitive to TPP inhibition under physiological TPP and potassium concentrations.
In 2022, a gain-of-function mutation in BCKDK (p.His162Gln) was identified in a neonate and his father, both showing a biochemical phenotype of a mild form of maple syrup urine disease with increased plasma branched-chain amino acids. Computational molecular dynamics simulations suggested the mutation reduces inhibitory binding to the protein, increasing BCKDK activity and thus inactivating BCKDC. The authors noted this is the first evidence of BCKDK involvement in a mild MSUD form and called for further data to elucidate the clinical relevance.
No clinical trial has tested a BCKDK inhibitor in patients with BCKDK deficiency or any other condition. The structural and biochemical data exist, but what is missing is funding for drug development, a suitable inhibitor molecule that works at physiological conditions, and any clinical trial design or patient stratification strategy.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Current Opinion in Clinical Nutrition & Metabolic Care · 2001 · 126 citations
Regulation of branched-chain amino acid catabolism: nutritional and hormonal regulation of activity and expression of the branched-chain α-keto acid dehydrogenase kinase
AbstractBranched-chain alpha-keto acid dehydrogenase kinase is responsible for the inactivation and phosphorylation of the branched-chain alpha-keto acid dehydrogenase complex, the enzyme that catalyses the committed step of branched-chain amino acid catabolism. The activity of the branched-chain alpha-keto acid dehydrogenase complex is inversely correlated with kinase activity, suggesting that the relative activity of the kinase is the primary regulator of the activity of the complex. It has been shown that kinase activity and expression are affected by nutritional states imposed by low-protein diet feeding, starvation, diabetes, and exercise. Evidence has also been presented that certain hormones, particularly insulin, glucocorticoid, thyroid hormone and female sex hormones, affect the activity and expression of the kinase. The findings indicate that nutritional and hormonal control of the activity and expression of branched-chain alpha-keto acid dehydrogenase kinase provides an important means of control of the activity of the branched-chain alpha-keto acid dehydrogenase complex, with inactivation serving to conserve branched-chain amino acids for protein synthesis in some situations and activation serving to provide carbon for gluconeogenesis in others.
Proceedings of the National Academy of Sciences · 2001 · 84 citations · open access
Structure of rat BCKD kinase: Nucleotide-induced domain communication in a mitochondrial protein kinase
AbstractMitochondrial protein kinases (mPKs) are molecular switches that down-regulate the oxidation of branched-chain alpha-ketoacids and pyruvate. Elevated levels of these metabolites are implicated in disease states such as insulin-resistant Type II diabetes, branched-chain ketoaciduria, and primary lactic acidosis. We report a three-dimensional structure of a member of the mPK family, rat branched-chain alpha-ketoacid dehydrogenase kinase (BCK). BCK features a characteristic nucleotide-binding domain and a four-helix bundle domain. These two domains are reminiscent of modules found in protein histidine kinases (PHKs), which are involved in two-component signal transduction systems. Unlike PHKs, BCK dimerizes through direct interaction of two opposing nucleotide-binding domains. Nucleotide binding to BCK is uniquely mediated by both potassium and magnesium. Binding of ATP induces disorder-order transitions in a loop region at the nucleotide-binding site. These structural changes lead to the formation of a quadruple aromatic stack in the interface between the nucleotide-binding domain and the four-helix bundle domain, where they induce a movement of the top portion of two helices. Phosphotransfer induces further ordering of the loop region, effectively trapping the reaction product ADP, which explains product inhibition in mPKs. The BCK structure is a prototype for all mPKs and will provide a framework for structure-assisted inhibitor design for this family of kinases.
Journal of Biological Chemistry · 1968 · 63 citations · open access
Branched Chain α-Keto Acid Metabolism
AbstractEvidence derived from physical, chemical, and kinetic studies of a partially purified branched chain α-keto acid dehydrogenase establishes that both α-ketoisocaproic and α-keto-β-methylvaleric acids are oxidatively decarboxylated by a single enzyme complex. This situation is consistent with the current clinical observations of branched chain ketoaciduria. The significance of this finding is discussed in relation to metabolic aspects of the disease.
A Gain-of-Function Mutation on BCKDK Gene and Its Possible Pathogenic Role in Branched-Chain Amino Acid Metabolism
AbstractBCKDK is an important key regulator of branched-chain ketoacid dehydrogenase complex activity by phosphorylating and so inactivating branched-chain ketoacid dehydrogenases, the rate-limiting enzyme of the branched-chain amino acid metabolism. We identified, by whole exome-sequencing analysis, the p.His162Gln variant of the BCKDK gene in a neonate, picked up by newborn screening, with a biochemical phenotype of a mild form of maple syrup urine disease (MSUD). The same biochemical and genetic picture was present in the father. Computational analysis of the mutation was performed to better understand its role. Extensive atomistic molecular dynamics simulations showed that the described mutation leads to a conformational change of the BCKDK protein, which reduces the effect of inhibitory binding bound to the protein itself, resulting in its increased activity with subsequent inactivation of BCKDC and increased plasmatic branched-chain amino acid levels. Our study describes the first evidence of the involvement of the BCKDK gene in a mild form of MSUD. Although further data are needed to elucidate the clinical relevance of the phenotype caused by this variant, awareness of this regulatory activation of BCKDK is very important, especially in newborn screening data interpretation.
Bioscience Biotechnology and Biochemistry · 2009 · 3 citations
Inhibition of Branched-Chain α-Ketoacid Dehydrogenase Kinase by Thiamine Pyrophosphate at Different Potassium Ionic Levels
AbstractInhibition of branched-chain alpha-ketoacid dehydrogenase kinase (BDK) by thiamine pyrophosphate (TPP) was analyzed at two potassium ion (K(+)) concentrations. IC(50) values of 4.6 and 8.0 microM and inhibition constant values of 3.2 and 16.4 microM were obtained in the presence of 20 and 100 mM K(+), respectively. These results suggest that BDK is less sensitive to TPP inhibition under physiological TPP and K(+) concentrations.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
