Phosphatidylcholine Formation by LPCAT1 is Regulated by Ca(2+) and the Redox Status of the Cell

Overview

Journal BMC Biochem

Publisher Biomed Central

Specialty Biochemistry

Date 2012 Jun 9

PMID 22676268

Citations 15

Authors

Eric Soupene

Frans A Kuypers

Affiliations

Soon will be listed here.

Abstract

Background: Unsaturated fatty acids are susceptible to oxidation and damaged chains are removed from glycerophospholipids by phospholipase A(2). De-acylated lipids are then re-acylated by lysophospholipid acyltransferase enzymes such as LPCAT1 which catalyses the formation of phosphatidylcholine (PC) from lysoPC and long-chain acyl-CoA.

Results: Activity of LPCAT1 is inhibited by Ca(2+), and a Ca(2+)-binding motif of the EF-hand type, EFh-1, was identified in the carboxyl-terminal domain of the protein. The residues Asp-392 and Glu-403 define the loop of the hairpin structure formed by EFh-1. Substitution of D(392) and E(403) to alanine rendered an enzyme insensitive to Ca(2+), which established that Ca(2+) binding to that region negatively regulates the activity of the acyltransferase amino-terminal domain. Residue Cys-211 of the conserved motif III is not essential for catalysis and not sufficient for sensitivity to treatment by sulfhydryl-modifier agents. Among the several active cysteine-substitution mutants of LPCAT1 generated, we identified one to be resistant to treatment by sulfhydryl-alkylating and sulfhydryl-oxidizer agents.

Conclusion: Mutant forms of LPCAT1 that are not inhibited by Ca(2+) and sulfhydryl-alkylating and -oxidizing agents will provide a better understanding of the physiological function of a mechanism that places the formation of PC, and the disposal of the bioactive species lysoPC, under the control of the redox status and Ca(2+) concentration of the cell.

Citing Articles

Pathological characteristics of axons and alterations of proteomic and lipidomic profiles in midbrain dopaminergic neurodegeneration induced by WDR45-deficiency.

Wang P, Shao Y, Al-Nusaif M, Zhang J, Yang H, Yang Y Mol Neurodegener. 2024; 19(1):62.

PMID: 39183331 PMC: 11346282. DOI: 10.1186/s13024-024-00746-4.

Dual Role of ACBD6 in the Acylation Remodeling of Lipids and Proteins.

Soupene E, Kuypers F Biomolecules. 2022; 12(12).

PMID: 36551154 PMC: 9775454. DOI: 10.3390/biom12121726.

LpCat1 Promotes Malignant Transformation of Hepatocellular Carcinoma Cells by Directly Suppressing STAT1.

Ji W, Peng Z, Sun B, Chen L, Zhang Q, Guo M Front Oncol. 2021; 11:678714.

PMID: 34178664 PMC: 8220817. DOI: 10.3389/fonc.2021.678714.

Cholesterol Deficiency Causes Impaired Osmotic Stability of Cultured Red Blood Cells.

Bernecker C, Kofeler H, Pabst G, Trotzmuller M, Kolb D, Strohmayer K Front Physiol. 2020; 10:1529.

PMID: 31920725 PMC: 6933518. DOI: 10.3389/fphys.2019.01529.

Phosphatidylserine decarboxylase CT699, lysophospholipid acyltransferase CT775, and acyl-ACP synthase CT776 provide membrane lipid diversity to Chlamydia trachomatis.

Soupene E, Kuypers F Sci Rep. 2017; 7(1):15767.

PMID: 29150677 PMC: 5693948. DOI: 10.1038/s41598-017-16116-8.

References

Shindou H, Hishikawa D, Harayama T, Yuki K, Shimizu T . Recent progress on acyl CoA: lysophospholipid acyltransferase research. J Lipid Res. 2008; 50 Suppl:S46-51. PMC: 2674719. DOI: 10.1194/jlr.R800035-JLR200. View

Arthur G, Choy P . Acylation of 1-alkenyl-glycerophosphocholine and 1-acyl-glycerophosphocholine in guinea pig heart. Biochem J. 1986; 236(2):481-7. PMC: 1146865. DOI: 10.1042/bj2360481. View

Kawasaki H, Kretsinger R . Calcium-binding proteins. 1: EF-hands. Protein Profile. 1994; 1(4):343-517. View

Yamashita A, Nakanishi H, Suzuki H, Kamata R, Tanaka K, Waku K . Topology of acyltransferase motifs and substrate specificity and accessibility in 1-acyl-sn-glycero-3-phosphate acyltransferase 1. Biochim Biophys Acta. 2007; 1771(9):1202-15. DOI: 10.1016/j.bbalip.2007.07.002. View

Gijon M, Riekhof W, Zarini S, Murphy R, Voelker D . Lysophospholipid acyltransferases and arachidonate recycling in human neutrophils. J Biol Chem. 2008; 283(44):30235-45. PMC: 2573059. DOI: 10.1074/jbc.M806194200. View

Agarwal A, Barnes R, Garg A . Functional characterization of human 1-acylglycerol-3-phosphate acyltransferase isoform 8: cloning, tissue distribution, gene structure, and enzymatic activity. Arch Biochem Biophys. 2006; 449(1-2):64-76. DOI: 10.1016/j.abb.2006.03.014. View

Myher J, Kuksis A, Pind S . Molecular species of glycerophospholipids and sphingomyelins of human erythrocytes: improved method of analysis. Lipids. 1989; 24(5):396-407. DOI: 10.1007/BF02535147. View

Rety S . EF-hand calcium-binding proteins. Curr Opin Struct Biol. 2000; 10(6):637-43. DOI: 10.1016/s0959-440x(00)00142-1. View

Tiffert T, Lew V . Apparent Ca2+ dissociation constant of Ca2+ chelators incorporated non-disruptively into intact human red cells. J Physiol. 1998; 505 ( Pt 2):403-10. PMC: 1160073. DOI: 10.1111/j.1469-7793.1997.403bb.x. View

10.

Falke J, Drake S, Hazard A, Peersen O . Molecular tuning of ion binding to calcium signaling proteins. Q Rev Biophys. 1994; 27(3):219-90. DOI: 10.1017/s0033583500003012. View

11.

Lands W, Hart P . METABOLISM OF GLYCEROLIPIDS. VI. SPECIFICITIES OF ACYL COENZYME A: PHOSPHOLIPID ACYLTRANSFERASES. J Biol Chem. 1965; 240:1905-11. View

12.

Cates M, Teodoro M, Phillips Jr G . Molecular mechanisms of calcium and magnesium binding to parvalbumin. Biophys J. 2002; 82(3):1133-46. PMC: 1301919. DOI: 10.1016/S0006-3495(02)75472-6. View

13.

Friedman J, Chang B, Krauth D, Lopez I, Waseem N, Hurd R . Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice. Proc Natl Acad Sci U S A. 2010; 107(35):15523-8. PMC: 2932565. DOI: 10.1073/pnas.1002897107. View

14.

Ikura M, Ames J . Genetic polymorphism and protein conformational plasticity in the calmodulin superfamily: two ways to promote multifunctionality. Proc Natl Acad Sci U S A. 2006; 103(5):1159-64. PMC: 1360552. DOI: 10.1073/pnas.0508640103. View

15.

Grabarek Z . Structural basis for diversity of the EF-hand calcium-binding proteins. J Mol Biol. 2006; 359(3):509-25. DOI: 10.1016/j.jmb.2006.03.066. View

16.

Butikofer P, Yee M, Schott M, Lubin B, Kuypers F . Generation of phosphatidic acid during calcium-loading of human erythrocytes. Evidence for a phosphatidylcholine-hydrolyzing phospholipase D. Eur J Biochem. 1993; 213(1):367-75. DOI: 10.1111/j.1432-1033.1993.tb17770.x. View

17.

Chen X, Hyatt B, Mucenski M, Mason R, Shannon J . Identification and characterization of a lysophosphatidylcholine acyltransferase in alveolar type II cells. Proc Natl Acad Sci U S A. 2006; 103(31):11724-9. PMC: 1544237. DOI: 10.1073/pnas.0604946103. View

18.

Nakanishi H, Shindou H, Hishikawa D, Harayama T, Ogasawara R, Suwabe A . Cloning and characterization of mouse lung-type acyl-CoA:lysophosphatidylcholine acyltransferase 1 (LPCAT1). Expression in alveolar type II cells and possible involvement in surfactant production. J Biol Chem. 2006; 281(29):20140-7. DOI: 10.1074/jbc.M600225200. View

19.

Yuki K, Shindou H, Hishikawa D, Shimizu T . Characterization of mouse lysophosphatidic acid acyltransferase 3: an enzyme with dual functions in the testis. J Lipid Res. 2008; 50(5):860-9. PMC: 2666172. DOI: 10.1194/jlr.M800468-JLR200. View

20.

Cheng L, Han X, Shi Y . A regulatory role of LPCAT1 in the synthesis of inflammatory lipids, PAF and LPC, in the retina of diabetic mice. Am J Physiol Endocrinol Metab. 2009; 297(6):E1276-82. PMC: 2793047. DOI: 10.1152/ajpendo.00475.2009. View