Researchers Unveil Dynamic Structure of Key Metabolic Enzyme Complex

Scientists have uncovered the intricate, adaptable architecture of the pyruvate dehydrogenase complex (PDHc), a critical enzyme that plays a central role in cellular energy production. Using advanced cryo-electron microscopy and tomography techniques, researchers from Tsinghua University, Shenzhen University, and King Abdullah University of Science and Technology discovered that PDHc's structure is far more dynamic than previously believed.

The study, published in Protein & Cell, demonstrates that PDHc's core forms a dodecahedral scaffold with 60 inner core domains. Contrary to traditional models of a rigid, symmetrical structure, the peripheral enzymes E1p and E3 actually form a flexible, irregular configuration that can rapidly adjust to metabolic demands.

This breakthrough has significant implications for understanding metabolic disorders. By revealing the complex's adaptive nature, researchers can now explore more precise therapeutic strategies for inherited metabolic syndromes and mitochondrial dysfunction. The novel imaging approach also establishes a new standard for visualizing large, dynamic protein assemblies.

Dr. Sai Li, a co-corresponding author, emphasized that what was once perceived as disorder is actually a sophisticated design feature allowing PDHc to efficiently respond to changing metabolic conditions. The research shows that, on average, 21 E1p and 13 E3 subunits exist per complex, with spatial distributions following a Gaussian profile.

The findings challenge decades of structural assumptions about this essential metabolic enzyme and provide a more nuanced understanding of how cellular energy conversion processes operate. By identifying flexible interaction sites within PDHc, researchers can now begin developing targeted interventions for related metabolic diseases.