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Silencing branched-chain ketoacid dehydrogenase kinase exacerbates doxorubicin induced cytotoxicity in triple-negative breast cancer cells

ABSTRACT: Silencing branched-chain ketoacid dehydrogenase kinase exacerbates doxorubicin induced cytotoxicity in triple-negative breast cancer cells

PROVIDER: PRJNA685647 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13258630_1.fastq.gz	Fastqsanger.gz
	SRR13258630_2.fastq.gz	Fastqsanger.gz
	SRR13258631_1.fastq.gz	Fastqsanger.gz
	SRR13258631_2.fastq.gz	Fastqsanger.gz
	SRR13258632_1.fastq.gz	Fastqsanger.gz

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Discovery of small molecule branched-chain ketoacid dehydrogenase kinase 23 (BDK) inhibitors with opposing effects on BDK protein levels

Project description:Branched chain ketoacid dehydrogenase kinase (BDK) was immunoprecipitated from hearts of mice that had been treated with BDK inhibitors or vehicle.

2023-02-21 | MSV000091341 | MassIVE

Silencing branched-chain ketoacid dehydrogenase kinase exacerbates doxorubicin induced cytotoxicity in triple-negative breast cancer cells

Project description:TO BE FILLED IN WITH ABSTRACT

2021-09-22 | GSE163297 | GEO

Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy

2012-07-18 | GSE39447 | GEO

Reprogramming CD8+ T- cell branched N-glycosylation limits exhaustion, enhancing cytotoxicity and tumor killing

Project description:Branched N-glycans regulate CD8+ T-cell cytotoxicity

| PRJEB94932 | ENA

Restoration of branched chain amino acid catabolism improves kidney function in preclinical cardiovascular-kidney-metabolic syndrome models

Project description:Patients with metabolic syndrome and heart failure (HF) often have accompanying kidney dysfunction, which was recently defined as cardiovascular-kidney-metabolic (CKM) syndrome. Prior metabolomics profiling of metabolic syndrome patients identified a plasma branched chain amino acid (BCAA) signature, and BCAAs are elevated in HF patient myocardium. The rate limiting step of BCAA catabolism is decarboxylation by branched chain ketoacid dehydrogenase enzyme (BCKDH), which is negatively regulated by BCKDH kinase (BCKDK or BDK), and BDK inhibitors improve metabolism and heart failure preclinically. Here we show that BCAA catabolic impairment is associated with and may be causal to CKM as treatment with the BDK inhibitor BT2 improved urine protein content, glomerular filtration rate, kidney hypertrophy, and kidney pathology in CKM models. Coadministration of BT2 and empagliflozin restored renal function and gene expression signatures and improved mitochondrial density and function, suggesting that BDK inhibition could represent a therapeutic avenue for CKM.

2025-06-01 | GSE263155 | GEO

Structural and biochemical characterization of human mitochondrial branched-chain ?-ketoacid dehydrogenase phosphatase.

Project description:The branched-chain ?-ketoacid dehydrogenase phosphatase (BDP) component of the human branched-chain ?-ketoacid dehydrogenase complex (BCKDC) has been expressed in Escherichia coli and purified in the soluble form. The monomeric BDP shows a strict dependence on Mn(2+) ions for phosphatase activity, whereas Mg(2+) and Ca(2+) ions do not support catalysis. Metal binding constants for BDP, determined by competition isothermal titration calorimetry, are 2.4 nm and 10 ?m for Mn(2+) and Mg(2+) ions, respectively. Using the phosphorylated decarboxylase component (p-E1b) of BCKDC as a substrate, BDP shows a specific activity of 68 nmol/min/mg. The Ca(2+)-independent binding of BDP to the 24-meric transacylase (dihydrolipoyl transacylase; E2b) core of BCKDC results in a 3-fold increase in the dephosphorylation rate of p-E1b. However, the lipoyl prosthetic group on E2b is not essential for BDP binding or E2b-stimulated phosphatase activity. Acidic residues in the C-terminal linker of the E2b lipoyl domain are essential for the interaction between BDP and E2b. The BDP structure was determined by x-ray crystallography to 2.4 Å resolution. The BDP structure is dominated by a central ?-sandwich. There are two protrusions forming a narrow cleft ?10 Å wide, which constitutes the active site. The carboxylate moieties of acidic residues Asp-109, Asp-207, Asp-298, and Asp-337 in the active-site cleft participate in binding two metal ions. Substitutions of these residues with alanine nullify BDP phosphatase activity. Alteration of the nearby Arg-104 increases the K(m) for p-E1b peptide by 60-fold, suggesting that this residue is critical for the recognition of the native p-E1b protein.

| S-EPMC3308798 | biostudies-literature

Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy

Project description:Autism is present in 1% of the population, yet treatments are extremely limited. We identified homozygous inactivating mutations in the BCKDK gene in families presenting with autism and epilepsy. The encoded branched chain ketoacid dehydrogenase kinase protein is responsible for phosphorylation-mediated inactivation of the E1-alpha subunit of branched chain ketoacid dehydrogenase, itself mutated in Maple Syrup Urine Disease (MSUD). Patients with homozygous BCKDK mutations display reductions in BCKDK mRNA and protein, E1-alpha phosphorylation and serum branched chain amino acids (BCAAs). Bckdk knockout mice show abnormal brain amino acids profiles and neurobehavioral defects, which are largely corrected by dietary BCAA supplementation. Thus autism presenting with epilepsy due to BCKDK mutations represent a new and potentially treatable disease. A 51 chip study that includes both human and mouse samples to investigate the expression changes that result in a mutation or knockout of the BCKDK gene. Starting with human fibroblasts from three affecteds and two controls, cells were converted into IPSs, then NPCs, and finally Neurons. Each of these cell types were used to view the expression changes between a cells with a BCKDK mutation versus controls. Finally, a mouse knockout was performed to verify consistency of the expression pattern differences between the BCKCK knockout and wild-type. Samples are labeled as Affected if the sample came from a patient with a BCKDK mutation and WildType otherwise. Samples were usually replicated once.

2012-07-17 | E-GEOD-39447 | biostudies-arrayexpress

Epigenomic profiling of fibroblasts from patients with Maple Syrup Urine Disease (MSUD) or control samples

Project description:Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder characterised by deficient activity of the branched-chain alpha-ketoacid dehydrogenase complex, required to metabolise the amino acids leucine, isoleucine and valine. Despite its profound metabolic implications, the molecular alterations underlying this metabolic impairment had not yet been elucidated. Here we performed a comprehensive epigenomic analysis including fibroblasts derived from a cohort of MSUD patients (9) and unaffected controls (5) using the Infinium HumanMethylation EPIC platform.

2024-12-31 | E-MTAB-13822 | biostudies-arrayexpress

Benzothiophene carboxylate derivatives as novel allosteric inhibitors of branched-chain ?-ketoacid dehydrogenase kinase.

Project description:The mitochondrial branched-chain ?-ketoacid dehydrogenase complex (BCKDC) is negatively regulated by reversible phosphorylation.BCKDC kinase (BDK) inhibitors that augment BCKDC flux have been shown to reduce branched-chain amino acid (BCAA) concentrations in vivo. In the present study, we employed high-throughput screens to identify compound 3,6- dichlorobenzo[b]thiophene-2-carboxylic acid (BT2) as a novel BDK inhibitor (IC(50) = 3.19 ?M). BT2 binds to the same site in BDK as other known allosteric BDK inhibitors, including (S)-?-cholorophenylproprionate ((S)-CPP). BT2 binding to BDK triggers helix movements in the N-terminal domain, resulting in the dissociation of BDK from the BCKDC accompanied by accelerated degradation of the released kinase in vivo. BT2 shows excellent pharmacokinetics (terminal T(1?2) = 730 min) and metabolic stability (no degradation in 240 min), which are significantly better than those of (S)-CPP. BT2, its analog 3-chloro-6-fluorobenzo[ b]thiophene-2-carboxylic acid (BT2F), and a prodrug of BT2 (i.e. N-(4-acetamido-1,2,5-oxadiazol-3-yl)-3,6-dichlorobenzo[ b]thiophene-2-carboxamide (BT3)) significantly increase residual BCKDC activity in cultured cells and primary hepatocytes from patients and a mouse model of maple syrup urine disease. Administration of BT2 at 20 mg/kg/day to wild-type mice for 1 week leads to nearly complete dephosphorylation and maximal activation of BCKDC in heart, muscle, kidneys, and liver with reduction in plasma BCAA concentrations. The availability of benzothiophene carboxylate derivatives as stable BDK inhibitors may prove useful for the treatment of metabolic disease caused by elevated BCAA concentrations.

| S-EPMC4110271 | biostudies-literature

Loss of the Drosophila branched-chain α-ketoacid dehydrogenase complex results in neuronal dysfunction.

Project description:Maple syrup urine disease (MSUD) is an inherited error in the metabolism of branched-chain amino acids (BCAAs) caused by a severe deficiency of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which ultimately leads to neurological disorders. The limited therapies, including protein-restricted diets and liver transplants, are not as effective as they could be for the treatment of MSUD due to the current lack of molecular insights into the disease pathogenesis. To address this issue, we developed a Drosophila model of MSUD by knocking out the dDBT gene, an ortholog of the human gene encoding the dihydrolipoamide branched chain transacylase (DBT) subunit of BCKDH. The homozygous dDBT mutant larvae recapitulate an array of MSUD phenotypes, including aberrant BCAA accumulation, developmental defects, poor mobile behavior and disrupted L-glutamate homeostasis. Moreover, the dDBT mutation causes neuronal apoptosis during the developmental progression of larval brains. The genetic and functional evidence generated by in vivo depletion of dDBT expression in the eye indicates severe impairment of retinal rhabdomeres. Further, the dDBT mutant shows elevated oxidative stress and higher lipid peroxidation accumulation in the larval brain. Therefore, we conclude from in vivo evidence that the loss of dDBT results in oxidative brain damage that may lead to neuronal cell death and contribute to aspects of MSUD pathology. Importantly, when the dDBT mutants were administrated with Metformin, the aberrances in BCAA levels and motor behavior were ameliorated. This intriguing outcome strongly merits the use of the dDBT mutant as a platform for developing MSUD therapies.This article has an associated First Person interview with the joint first authors of the paper.

| S-EPMC7473638 | biostudies-literature

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