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Omega-3 versus Omega-6 fatty acid availability is controlled by hydrophobic site geometries of phospholipase A(2)s
Human phospholipase A(2)s (PLA(2)) constitute a superfamily of enzymes that hydrolyze the sn-2 acyl-chain of glycerophospholipids, producing lysophospholipids and free fatty acids. Each PLA(2) enzyme type contributes to specific biological functions based on its expression, subcellular localization,...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551542/ https://www.ncbi.nlm.nih.gov/pubmed/34474084 http://dx.doi.org/10.1016/j.jlr.2021.100113 |
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author | Hayashi, Daiki Mouchlis, Varnavas D. Dennis, Edward A. |
author_facet | Hayashi, Daiki Mouchlis, Varnavas D. Dennis, Edward A. |
author_sort | Hayashi, Daiki |
collection | PubMed |
description | Human phospholipase A(2)s (PLA(2)) constitute a superfamily of enzymes that hydrolyze the sn-2 acyl-chain of glycerophospholipids, producing lysophospholipids and free fatty acids. Each PLA(2) enzyme type contributes to specific biological functions based on its expression, subcellular localization, and substrate specificity. Among the PLA(2) superfamily, the cytosolic cPLA(2) enzymes, calcium-independent iPLA(2) enzymes, and secreted sPLA(2) enzymes are implicated in many diseases, but a central issue is the preference for double-bond positions in polyunsaturated fatty acids (PUFAs) occupying the sn-2 position of membrane phospholipids. We demonstrate that each PLA(2) has a unique preference between the specific omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the omega-6 arachidonic acid (AA), which are the precursors of most proinflammatory and anti-inflammatory or resolving eicosanoids and related oxylipins. Surprisingly, we discovered that human cPLA(2) selectively prefers AA, whereas iPLA(2) prefers EPA, and sPLA(2) prefers DHA as substrate. We determined the optimal binding of each phospholipid substrate in the active site of each PLA(2) to explain these specificities. To investigate this, we utilized recently developed lipidomics-based LC-MS/MS and GC/MS assays to determine the sn-2 acyl chain specificity in mixtures of phospholipids. We performed μs timescale molecular dynamics (MD) simulations to reveal unique active site properties, especially how the precise hydrophobic cavity accommodation of the sn-2 acyl chain contributes to the stability of substrate binding and the specificity of each PLA(2) for AA, EPA, or DHA. This study provides the first comprehensive picture of the unique substrate selectivity of each PLA(2) for omega-3 and omega-6 fatty acids. |
format | Online Article Text |
id | pubmed-8551542 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-85515422021-11-04 Omega-3 versus Omega-6 fatty acid availability is controlled by hydrophobic site geometries of phospholipase A(2)s Hayashi, Daiki Mouchlis, Varnavas D. Dennis, Edward A. J Lipid Res Research Article Human phospholipase A(2)s (PLA(2)) constitute a superfamily of enzymes that hydrolyze the sn-2 acyl-chain of glycerophospholipids, producing lysophospholipids and free fatty acids. Each PLA(2) enzyme type contributes to specific biological functions based on its expression, subcellular localization, and substrate specificity. Among the PLA(2) superfamily, the cytosolic cPLA(2) enzymes, calcium-independent iPLA(2) enzymes, and secreted sPLA(2) enzymes are implicated in many diseases, but a central issue is the preference for double-bond positions in polyunsaturated fatty acids (PUFAs) occupying the sn-2 position of membrane phospholipids. We demonstrate that each PLA(2) has a unique preference between the specific omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the omega-6 arachidonic acid (AA), which are the precursors of most proinflammatory and anti-inflammatory or resolving eicosanoids and related oxylipins. Surprisingly, we discovered that human cPLA(2) selectively prefers AA, whereas iPLA(2) prefers EPA, and sPLA(2) prefers DHA as substrate. We determined the optimal binding of each phospholipid substrate in the active site of each PLA(2) to explain these specificities. To investigate this, we utilized recently developed lipidomics-based LC-MS/MS and GC/MS assays to determine the sn-2 acyl chain specificity in mixtures of phospholipids. We performed μs timescale molecular dynamics (MD) simulations to reveal unique active site properties, especially how the precise hydrophobic cavity accommodation of the sn-2 acyl chain contributes to the stability of substrate binding and the specificity of each PLA(2) for AA, EPA, or DHA. This study provides the first comprehensive picture of the unique substrate selectivity of each PLA(2) for omega-3 and omega-6 fatty acids. American Society for Biochemistry and Molecular Biology 2021-08-30 /pmc/articles/PMC8551542/ /pubmed/34474084 http://dx.doi.org/10.1016/j.jlr.2021.100113 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Hayashi, Daiki Mouchlis, Varnavas D. Dennis, Edward A. Omega-3 versus Omega-6 fatty acid availability is controlled by hydrophobic site geometries of phospholipase A(2)s |
title | Omega-3 versus Omega-6 fatty acid availability is controlled by hydrophobic site geometries of phospholipase A(2)s |
title_full | Omega-3 versus Omega-6 fatty acid availability is controlled by hydrophobic site geometries of phospholipase A(2)s |
title_fullStr | Omega-3 versus Omega-6 fatty acid availability is controlled by hydrophobic site geometries of phospholipase A(2)s |
title_full_unstemmed | Omega-3 versus Omega-6 fatty acid availability is controlled by hydrophobic site geometries of phospholipase A(2)s |
title_short | Omega-3 versus Omega-6 fatty acid availability is controlled by hydrophobic site geometries of phospholipase A(2)s |
title_sort | omega-3 versus omega-6 fatty acid availability is controlled by hydrophobic site geometries of phospholipase a(2)s |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551542/ https://www.ncbi.nlm.nih.gov/pubmed/34474084 http://dx.doi.org/10.1016/j.jlr.2021.100113 |
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