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Structural basis for catalysis and selectivity of phospholipid synthesis by eukaryotic choline-phosphotransferase

Author

Listed:
  • Jacquelyn R. Roberts

    (University of Michigan
    University of Michigan School of Medicine)

  • Yasuhiro Horibata

    (Mibu)

  • Frank E. Kwarcinski

    (University of Michigan School of Medicine)

  • Vinson Lam

    (University of Michigan)

  • Ashleigh M. Raczkowski

    (University of Michigan)

  • Akane Hubbard

    (University of Michigan)

  • Betsy White

    (Stanford University)

  • Hiroyuki Sugimoto

    (Mibu)

  • Gregory G. Tall

    (University of Michigan School of Medicine)

  • Melanie D. Ohi

    (University of Michigan
    University of Michigan School of Medicine)

  • Shoji Maeda

    (University of Michigan School of Medicine
    Xaira Therapeutics)

Abstract

Phospholipids are the most abundant component in lipid membranes and are essential for the structural and functional integrity of the cell. In eukaryotic cells, phospholipids are primarily synthesized de novo through the Kennedy pathway that involves multiple enzymatic processes. The terminal reaction is mediated by a group of cytidine-5′-diphosphate (CDP)-choline /CDP-ethanolamine-phosphotransferases (CPT/EPT) that use 1,2-diacylglycerol (DAG) and CDP-choline or CDP-ethanolamine to produce phosphatidylcholine (PC) or phosphatidylethanolamine (PE) that are the main phospholipids in eukaryotic cells. Here we present the structure of the yeast CPT1 in multiple substrate-bound states. Structural and functional analysis of these binding-sites reveal the critical residues for the DAG acyl-chain preference and the choline/ethanolamine selectivity. Additionally, we present the structure in complex with a potent inhibitor characterized in this study. The ensemble of structures allows us to propose the reaction mechanism for phospholipid biosynthesis by the family of CDP-alcohol phosphotransferases (CDP-APs).

Suggested Citation

  • Jacquelyn R. Roberts & Yasuhiro Horibata & Frank E. Kwarcinski & Vinson Lam & Ashleigh M. Raczkowski & Akane Hubbard & Betsy White & Hiroyuki Sugimoto & Gregory G. Tall & Melanie D. Ohi & Shoji Maeda, 2025. "Structural basis for catalysis and selectivity of phospholipid synthesis by eukaryotic choline-phosphotransferase," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55673-1
    DOI: 10.1038/s41467-024-55673-1
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