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12 results for “Mitochondrial pyruvate carrier”
Key features of inhibitor binding to the human mitochondrial pyruvate carrier hetero-dimer
<p><span><span><span><span><strong><em>Objective</em></strong>: The mitochondrial pyruvate carrier (MPC) has emerged as a promising drug target for metabolic disorders, including non-alcoholic steatohepatitis and diabetes, metabolically dependent cancers and neurodegenerative diseases. A range of structurally diverse small molecule inhibitors have been proposed but the nature of their interaction with MPC is not understood. Moreover, the composition of the functional human MPC is still debated. The goal of this study was to characterize the human MPC protein <em>in vitro</em>, to understand the chemical features that determine binding of structurally diverse inhibitors and to develop novel higher affinity ones.</span></span></span></span></p> <p><span><span><span><span><strong><em>Results</em></strong>: We have determined that the functional unit of human MPC is a hetero-dimer. We have compared all different classes of MPC inhibitors to find that three closely arranged hydrogen bond acceptors followed by an aromatic ring are shared characteristics of all inhibitors and represent the minimal requirement for high potency. We also demonstrate that high affinity binding is not attributed to covalent bond formation with MPC cysteines, as previously proposed. Following the basic pharmacophore properties, we identify 14 new inhibitors of MPC, one outperforming compound UK5099 by tenfold. Two of them are the commonly prescribed drugs entacapone and nitrofurantoin, suggesting an off-target mechanism associated with their adverse effects. </span></span></span></span></p> <p><span><span><span><span><strong><em>Conclusion</em></strong>: This work defines the composition of human MPC and the essential MPC inhibitor characteristics. In combination with the functional assays we describe, this new understanding will accelerate the development of clinically relevant MPC modulators.</span></span></span></span></p>
Key features of inhibitor binding to the human mitochondrial pyruvate carrier hetero-dimer
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Data from: The yeast mitochondrial pyruvate carrier is a hetero-dimer in its functional state
The mitochondrial pyruvate carrier (MPC) is critical for cellular homeostasis, as it is required in central metabolism for transporting pyruvate from the cytosol into the mitochondrial matrix. MPC has been implicated in many diseases and is being investigated as a drug target. A few years ago, small membrane proteins, called MPC1 and MPC2 in mammals and Mpc1, Mpc2 and Mpc3 in yeast, were proposed to form large protein complexes responsible for this function. However, the MPC complexes have never been isolated and their composition, oligomeric state and functional properties have not been defined. Here, we identify the functional unit of MPC from Saccharomyces cerevisiae. In contrast to earlier hypotheses, we demonstrate that MPC is a hetero‐dimer, not a multimeric complex. When not engaged in hetero‐dimers, the yeast Mpc proteins can also form homo‐dimers that are, however, inactive. We show that the earlier described substrate transport properties and inhibitor profiles are embodied by the hetero‐dimer. This work provides a foundation for elucidating the structure of the functional complex and the mechanism of substrate transport and inhibition.
Data from: The yeast mitochondrial pyruvate carrier is a hetero-dimer in its functional state
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The mitochondrial pyruvate carrier regulates antitumor function and memory T cell differentiation
GEO Series GSE184718. Mus musculus. 5 samples. Type: Genome binding/occupancy profiling by high throughput sequencing.
Transcriptomic analysis of acute mitochondrial pyruvate carrier inhibition using UK5099 in ABL prostate cancer cells
GEO Series GSE114708. Homo sapiens. 6 samples. Type: Expression profiling by high throughput sequencing.
RNA sequencing of PTEN,Rb1 double knockout (DKO) mouse prostate organoids treated with vehicle or the small molecule mitochondrial pyruvate carrier (MPC) inhibitor UK5099
GEO Series GSE221021. Mus musculus. 6 samples. Type: Expression profiling by high throughput sequencing.
Mitochondrial Pyruvate Carrier 1 (MPC1) enforces T cell homeostasis by enabling pyruvate oxidation in the mitochondria
GEO Series GSE122711. Mus musculus. 20 samples. Type: Expression profiling by high throughput sequencing.
Mitochondrial Pyruvate Carrier 1 (MPC1) promotes peripheral T cell quiescence through metabolic regulation of thymic development
GEO Series GSE138718. Mus musculus. 6 samples. Type: Expression profiling by high throughput sequencing.
Mitochondrial carrier homolog 2 (MTCH2) regulates the differentiation of AML cells by controlling pyruvate entry into the mitochondria, nuclear localization of pyruvate dehydrogenase complex and H3 an
GEO Series GSE103834. Homo sapiens. 8 samples. Type: Expression profiling by high throughput sequencing.
ATAC-sequencing of primary basal-derived mouse prostate organoids treated with vehicle, the mitochondrial pyruvate carrier inhibitor UK5099, or lactate supplementation
GEO Series GSE221442. Mus musculus. 3 samples. Type: Genome binding/occupancy profiling by high throughput sequencing.
Loss of the mitochondrial pyruvate carrier promotes stem cell gene expression in colon adenomas.
GEO Series GSE136710. Mus musculus. 109 samples. Type: Other.
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DANDI Archive for NWB datasets
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