The role of metabolism in shaping enzyme structures over 400 million years.

Journal: Nature
Published Date: Jul 9, 2025

Abstract

Advances in deep learning and AlphaFold2 have enabled the large-scale prediction of protein structures across species, opening avenues for studying protein function and evolution. Here we analyse 11,269 predicted and experimentally determined enzyme structures that catalyse 361 metabolic reactions across 225 pathways to investigate metabolic evolution over 400 million years in the Saccharomycotina subphylum. By linking sequence divergence in structurally conserved regions to a variety of metabolic properties of the enzymes, we reveal that metabolism shapes structural evolution across multiple scales, from species-wide metabolic specialization to network organization and the molecular properties of the enzymes. Although positively selected residues are distributed across various structural elements, enzyme evolution is constrained by reaction mechanisms, interactions with metal ions and inhibitors, metabolic flux variability and biosynthetic cost. Our findings uncover hierarchical patterns of structural evolution, in which structural context dictates amino acid substitution rates, with surface residues evolving most rapidly and small-molecule-binding sites evolving under selective constraints without cost optimization. By integrating structural biology with evolutionary genomics, we establish a model in which enzyme evolution is intrinsically governed by catalytic function and shaped by metabolic niche, network architecture, cost and molecular interactions.

Authors

  • Oliver Lemke
    Department of Biochemistry, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • Benjamin Murray Heineike
    Department of Biochemistry, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • Sandra Viknander
    Department of Life Sciences, Chalmers University of Technology, Gothenburg, Sweden.
  • Nir Cohen
    Department of Biochemistry, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • Feiran Li
  • Jacob Lucas Steenwyk
    Howard Hughes Medical Institute, University of California Berkeley, Berkeley, CA, USA.
  • Leonard Spranger
    Department of Biochemistry, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • Federica Agostini
    Center for Chronic Intestinal Failure, St Orsola Hospital, University of Bologna, Bologna, Italy; School of Medicine of the University of Bologna, Bologna, Italy.
  • Cory Thomas Lee
    Department of Biochemistry, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • Simran Kaur Aulakh
    Center for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Judith Berman
    School of Molecular Cell Biology and Biotechnology, Department of Molecular Microbiology and Biotechnology, George Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel jberman@tauex.tau.ac.il.
  • Antonis Rokas
    Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA.
  • Jens Nielsen
    Department of Biology and Biological Engineering , Chalmers University of Technology , SE-412 96 Gothenburg , Sweden.
  • Toni Ingolf Gossmann
    Faculty of Biochemical and Chemical Engineering, TU Dortmund University, Dortmund, Germany.
  • Aleksej Zelezniak
    Department of Biology and Biological Engineering, Chalmers University of Technology, Kemivägen 10, SE-412 96, Gothenburg, Sweden. aleksej.zelezniak@chalmers.se.
  • Markus Ralser
    The Francis Crick Institute, Molecular Biology of Metabolism laboratory, London, UK. markus.ralser@crick.ac.uk.

Keywords

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