️ 75: Metabolic Shaping of Enzyme Structures Over 400 Million Years

️ Episode 75: Metabolic Shaping of Enzyme Structures Over 400 Million Years In this episode of PaperCast Base by Base, we explore a large-scale study published in Nature by Lemke et al. that leverages AlphaFold2-predicted and experimentally determined enzyme structures across 27 yeast species to reveal how metabolic properties have constrained and shaped enzyme structural evolution over 400 million years in the Saccharomycotina subphylum. Study Highlights:The authors analyzed over 11,000 enzyme structures across diverse yeast species to link sequence divergence in conserved regions to metabolic flux, enzyme abundance, and pathway membership. They found that enzymes in central metabolism, oxidoreductases, and metal-binding proteins exhibit high structural conservation, whereas hydrolases and peripheral pathway enzymes are more divergent. Variability in metabolic flux and catalytic rates, rather than absolute values, was more predictive of structural divergence across species. The study also uncovered a hierarchy of cost optimization, showing that surface residues are preferentially optimized for biosynthetic cost while binding sites remain highly constrained. Finally, clusters of fully conserved residues were found to correspond to small-molecule and protein–protein interaction sites, highlighting functional hotspots. Conclusion:This integrative structural genomics approach reveals how catalytic function and metabolic context govern enzyme evolution and offers new avenues for enzyme annotation and metabolic engineering. Reference:Lemke O, Heineike BM, Viknander S, Cohen N, Li F, Steenwyk JL, Spranger L, Agostini F, Lee CT, Aulakh SK, Berman J, Rokas A, Nielsen J, Gossmann TI, Zelezniak A & Ralser M. The role of metabolism in shaping enzyme structures over 400 million years. Nature. 2025. doi:10.1038/s41586-025-09205-6 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

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