The Pyruvate Dehydrogenase Complex: A 90-Year-Old Enigma Shaping the Future of Structural Enzymology.

The ancient pyruvate dehydrogenase complex (PDHc) performs the "link reaction" of cellular respiration-a discovery from the 1930s that was central in the award of the 1953 Nobel Prize in Physiology and Medicine to Krebs and Lipmann. Fast forward to 2024, PDHc emerges with roles in Alzheimer's, cancer, and neurodegeneration, as well as in obesity and aging processes. Due to these recent reports, structural analysis of PDHc, a 10-megadalton enzymatic complex, comes into focus-only now this analysis begins to unveil an enormous and challenging molecular complexity. Cutting-edge techniques and methods, such as cryo-electron microscopy (cryo-EM), cross-linking (XL) and mass spectrometry (MS), advanced molecular and biochemical analysis, and computational structural biology, powered by artificial intelligence (AI), converge to systematically probe the mechanistic details governing PDHc function. This chapter collects and updates the knowledge in PDHc structure and function and pinpoints unresolved questions, with the hope of not waiting another 90 years for their answer.