Kun WangCHIA-WEI LEEXuewu SuiSiyoung KimShuhui WangAidan B. HiggsAaron J. BaublisGregory VothMaofu LiaoTobias WaltherRobert Farese2023-07-242023-07-242023-06-142041-1723https://scholars.lib.ntu.edu.tw/handle/123456789/634047<jats:title>Abstract</jats:title><jats:p>Cells remodel glycerophospholipid acyl chains via the Lands cycle to adjust membrane properties. Membrane-bound <jats:italic>O</jats:italic>-acyltransferase (MBOAT) 7 acylates lyso-phosphatidylinositol (lyso-PI) with arachidonyl-CoA. <jats:italic>MBOAT7</jats:italic> mutations cause brain developmental disorders, and reduced expression is linked to fatty liver disease. In contrast, increased <jats:italic>MBOAT7</jats:italic> 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.</jats:p>enjournal article10.1038/s41467-023-38932-5373165132-s2.0-85162072496http://dx.doi.org/10.1038/s41467-023-38932-5139081424