8erc

Human Membrane-bound O-acyltransferase 7Human Membrane-bound O-acyltransferase 7

Structural highlights

8erc is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.7Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MBOA7_HUMAN Autosomal recessive non-syndromic intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Function

MBOA7_HUMAN Acyltransferase which catalyzes the transfer of an acyl group from an acyl-CoA to a lysophosphatidylinositol (1-acylglycerophosphatidylinositol or LPI) leading to the production of a phosphatidylinositol (1,2-diacyl-sn-glycero-3-phosphoinositol or PI) and participates in the reacylation step of the phospholipid remodeling pathway also known as the Lands cycle (PubMed:18772128, PubMed:18094042). Prefers arachidonoyl-CoA as the acyl donor, thus contributing to the regulation of free levels arachidonic acid in cell (PubMed:18772128, PubMed:18094042). In liver, participates in the regulation of triglyceride metabolism through the phosphatidylinositol acyl-chain remodeling regulation (PubMed:32253259).^[1] ^[2] ^[3]

Publication Abstract from PubMed

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.

The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification.,Wang K, Lee CW, Sui X, Kim S, Wang S, Higgs AB, Baublis AJ, Voth GA, Liao M, Walther TC, Farese RV Jr Nat Commun. 2023 Jun 14;14(1):3533. doi: 10.1038/s41467-023-38932-5. PMID:37316513^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lee HC, Inoue T, Imae R, Kono N, Shirae S, Matsuda S, Gengyo-Ando K, Mitani S, Arai H. Caenorhabditis elegans mboa-7, a member of the MBOAT family, is required for selective incorporation of polyunsaturated fatty acids into phosphatidylinositol. Mol Biol Cell. 2008 Mar;19(3):1174-84. PMID:18094042 doi:10.1091/mbc.e07-09-0893
↑ Gijón MA, Riekhof WR, Zarini S, Murphy RC, Voelker DR. Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils. J Biol Chem. 2008 Oct 31;283(44):30235-45. PMID:18772128 doi:10.1074/jbc.M806194200
↑ Tanaka Y, Shimanaka Y, Caddeo A, Kubo T, Mao Y, Kubota T, Kubota N, Yamauchi T, Mancina RM, Baselli G, Luukkonen P, Pihlajamäki J, Yki-Järvinen H, Valenti L, Arai H, Romeo S, Kono N. LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover. Gut. 2021 Jan;70(1):180-193. PMID:32253259 doi:10.1136/gutjnl-2020-320646
↑ Wang K, Lee CW, Sui X, Kim S, Wang S, Higgs AB, Baublis AJ, Voth GA, Liao M, Walther TC, Farese RV Jr. The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification. Nat Commun. 2023 Jun 14;14(1):3533. PMID:37316513 doi:10.1038/s41467-023-38932-5

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OCA

[1] Lee HC, Inoue T, Imae R, Kono N, Shirae S, Matsuda S, Gengyo-Ando K, Mitani S, Arai H. Caenorhabditis elegans mboa-7, a member of the MBOAT family, is required for selective incorporation of polyunsaturated fatty acids into phosphatidylinositol. Mol Biol Cell. 2008 Mar;19(3):1174-84. PMID:18094042 doi:10.1091/mbc.e07-09-0893

[2] Gijón MA, Riekhof WR, Zarini S, Murphy RC, Voelker DR. Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils. J Biol Chem. 2008 Oct 31;283(44):30235-45. PMID:18772128 doi:10.1074/jbc.M806194200

[3] Tanaka Y, Shimanaka Y, Caddeo A, Kubo T, Mao Y, Kubota T, Kubota N, Yamauchi T, Mancina RM, Baselli G, Luukkonen P, Pihlajamäki J, Yki-Järvinen H, Valenti L, Arai H, Romeo S, Kono N. LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover. Gut. 2021 Jan;70(1):180-193. PMID:32253259 doi:10.1136/gutjnl-2020-320646

[4] Wang K, Lee CW, Sui X, Kim S, Wang S, Higgs AB, Baublis AJ, Voth GA, Liao M, Walther TC, Farese RV Jr. The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification. Nat Commun. 2023 Jun 14;14(1):3533. PMID:37316513 doi:10.1038/s41467-023-38932-5

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8erc

Human Membrane-bound O-acyltransferase 7Human Membrane-bound O-acyltransferase 7

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

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8erc

Human Membrane-bound O-acyltransferase 7Human Membrane-bound O-acyltransferase 7

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

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