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

Wang, Kun1,2; Lee, Chia-Wei1,2; Sui, Xuewu1,2,10; Kim, Siyoung3; Wang, Shuhui2; Higgs, Aidan B.1,2; Baublis, Aaron J.1,2,4; Voth, Gregory A.5,6; Liao, Maofu1,2,7; Walther, Tobias C.1,2,4,8,9,11; Farese, Robert V.1,2,8,11

2023-06-14

10.1038/s41467-023-38932-5

NATURE COMMUNICATIONS   影响因子和分区

2041-1723

["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.","Wang et al. report a structure for human MBOAT7, the enzyme responsible for remodeling acyl chains of phosphatidylinositol. The structure enabled the identification of MBOAT7 inhibitors and provides insights into substrate specificity among MBOATs."]

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NSF[DMR-182869] ; null[R01GM063796] ; null[R01GM141050]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:001048208600006

NATURE PORTFOLIO

2-s2.0-85162072496

Web of Science

1.Harvard T H Chan Sch Publ Hlth, Dept Mol Metab, Boston, MA USA
2.Harvard Med Sch, Dept Cell Biol, Boston, MA USA
3.Univ Chicago, Pritzker Sch Mol Engn, Chicago, IL USA
4.Harvard T H Chan Sch Publ Hlth, Harvard T H Chan Adv Multi Omics Platform, Boston, MA USA
5.Univ Chicago, Dept Chem, Chicago Ctr Theoret Chem, James Franck Inst, Chicago, IL USA
6.Univ Chicago, Inst Biophys Dynam, Chicago, IL USA
7.Southern Univ Sci & Technol, Sch Life Sci, Shenzhen, Peoples R China
8.Broad Inst MIT & Harvard, Cambridge, MA USA
9.Howard Hughes Med Inst, Boston, MA USA
10.Texas A&M Univ, Dept Biochem & Biophys, Coll Stn, TX USA
11.Sloan Kettering Inst, Cell Biol Program, Mem Sloan Kettering Canc Ctr, New York, NY USA

Wang, Kun,Lee, Chia-Wei,Sui, Xuewu,et al. The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification[J]. NATURE COMMUNICATIONS,2023,14(1).

Wang, Kun.,Lee, Chia-Wei.,Sui, Xuewu.,Kim, Siyoung.,Wang, Shuhui.,...&Farese, Robert V..(2023).The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification.NATURE COMMUNICATIONS,14(1).

Wang, Kun,et al."The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification".NATURE COMMUNICATIONS 14.1(2023).