{"doi":"10.1016/j.jlr.2021.100113","title":"Omega-3 versus Omega-6 fatty acid availability is controlled by hydrophobic site geometries of phospholipase A2s","abstract":"Human phospholipase A 2 s (PLA 2 ) constitute a superfamily of enzymes that hydrolyze the sn-2 acylchain 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 s 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.","journal":"Journal of Lipid Research","year":2021,"id":153765,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":67,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":515990,"name":"Varnavas D. Mouchlis","orcid":"0000-0002-4235-1867","position":1,"is_corresponding":false},{"id":108033,"name":"Edward A. Dennis","orcid":"0000-0003-3738-3140","position":2,"is_corresponding":false},{"id":515989,"name":"Daiki Hayashi","orcid":"0000-0002-2616-448X","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-18T23:43:44.759273Z","pmid":"34474084","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}