Identification of a novel compound that induces oligomer disassembly of the pyruvate dehydrogenase E2 complex

The pyruvate dehydrogenase complex (PDC) is a multienzyme system that links glycolysis to the tricarboxylic acid cycle via oxidative decarboxylation of pyruvate. Among its catalytic components, the E2 subunit forms a 60-mer oligomeric core that provides both structural and functional support. While PDC activity is classically regulated through phosphorylation of the E1α subunit by pyruvate dehydrogenase kinase, this mechanism often fails under pathological conditions such as pancreatic ductal adenocarcinoma (PDAC), where E2 is frequently overexpressed, resulting in sustained enzymatic activity. To counteract this excessive activation of PDC, we explored a chemical approach capable of destabilizing the structural integrity of the E2 complex. We identified a novel compound through functional screening of candidate molecules that induces structural disassembly of the E2 oligomer. Direct visualization analysis by transmission electron microscopy revealed that this compound markedly reduced intact 60-mer populations and increased smaller oligomeric forms. The disassembly phenomenon was further validated by chromatographic separation and crosslinking assays. These findings demonstrate that the quaternary structure of the E2 core is chemically modulatable and establish a foundation for non-genetic strategies to alter PDC assembly. Such modulation provides a valuable tool for investigating structure-function relationships in large enzymatic complexes and may inform future therapeutic development.