The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification

Kun Wang, Chia-Wei Lee, Xuewu Sui, Siyoung Kim, Shuhui Wang, Aidan B. Higgs, Aaron J. Baublis, Gregory A. Voth, Maofu Liao (), Tobias C. Walther () and Robert V. Farese ()
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Kun Wang: Harvard T.H. Chan School of Public Health
Chia-Wei Lee: Harvard T.H. Chan School of Public Health
Xuewu Sui: Harvard T.H. Chan School of Public Health
Siyoung Kim: University of Chicago
Shuhui Wang: Harvard Medical School
Aidan B. Higgs: Harvard T.H. Chan School of Public Health
Aaron J. Baublis: Harvard T.H. Chan School of Public Health
Gregory A. Voth: The University of Chicago
Maofu Liao: Harvard Medical School
Tobias C. Walther: Harvard T.H. Chan School of Public Health
Robert V. Farese: Harvard T.H. Chan School of Public Health

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Cells remodel glycerophospholipid acyl chains via the Lands cycle to adjust membrane properties. Membrane-bound O-acyltransferase (MBOAT) 7 acylates lyso-phosphatidylinositol (lyso-PI) with arachidonyl-CoA. MBOAT7 mutations cause brain developmental disorders, and reduced expression is linked to fatty liver disease. In contrast, increased MBOAT7 expression is linked to hepatocellular and renal cancers. The mechanistic basis of MBOAT7 catalysis and substrate selectivity are unknown. Here, we report the structure and a model for the catalytic mechanism of human MBOAT7. Arachidonyl-CoA and lyso-PI access the catalytic center through a twisted tunnel from the cytosol and lumenal sides, respectively. N-terminal residues on the ER lumenal side determine phospholipid headgroup selectivity: swapping them between MBOATs 1, 5, and 7 converts enzyme specificity for different lyso-phospholipids. Finally, the MBOAT7 structure and virtual screening enabled identification of small-molecule inhibitors that may serve as lead compounds for pharmacologic development.

Date: 2023
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DOI: 10.1038/s41467-023-38932-5

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