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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,...

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Autores principales: Hayashi, Daiki, Mouchlis, Varnavas D., Dennis, Edward A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
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.
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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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