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Bioorthogonal chemistry has revolutionized how phospholipid biosynthesis, transport, and turnover are studied, with clickable metabolic precursors now available for several phospholipid classes. Yet no metabolic bioorthogonal probe for labeling endogenous PE and PE\u2010derived protein modifications has been developed. Here, we introduce an alkyne\u2010tagged ethanolamine analog (AlkEA) that is incorporated into PE via the Kennedy pathway and can be derivatized by copper\u2010catalyzed azide\u2013alkyne cycloaddition (CuAAC) for visualization and affinity enrichment. Confocal microscopy revealed the subcellular distribution of AlkEA\u2010labeled PE in the ER, Golgi, mitochondria, and autophagosomes, while lipidomic analysis demonstrated AlkEA incorporation across diverse PE species. AlkEA labeling also allowed affinity isolation of PE\u2010conjugated LC3 and ubiquitin, as well as that of a prototypical GPI\u2010anchored protein. AlkEA is thus a minimally perturbing tool broadly applicable to dissecting PE metabolism and PE\u2010dependent protein modifications.<\/jats:p>","DOI":"10.1002\/anie.1866870","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T11:28:16Z","timestamp":1786015696000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Bioorthogonal Tools for Ethanolamine Lipids and Protein Conjugates"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5465-6863","authenticated-orcid":false,"given":"Yuan\u2010Ting","family":"Cho","sequence":"first","affiliation":[{"name":"Weill Institute for Cell and Molecular Biology Cornell University  Ithaca New York USA"},{"name":"Department of Chemistry and Chemical Biology Cornell University  Ithaca New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy Y.","family":"Jao","sequence":"additional","affiliation":[{"name":"Department of Cell Biology Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijun","family":"Xia","sequence":"additional","affiliation":[{"name":"Weill Institute for Cell and Molecular Biology Cornell University  Ithaca New York USA"},{"name":"Department of Chemistry and Chemical Biology Cornell University  Ithaca New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0597-7246","authenticated-orcid":false,"given":"Brittany M.","family":"White\u2010Mathieu","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of New Hampshire  Durham New Hampshire USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0748-9545","authenticated-orcid":false,"given":"Adrian","family":"Salic","sequence":"additional","affiliation":[{"name":"Department of Cell Biology Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2939-3138","authenticated-orcid":false,"given":"Jeremy M.","family":"Baskin","sequence":"additional","affiliation":[{"name":"Weill Institute for Cell and Molecular Biology Cornell University  Ithaca New York USA"},{"name":"Department of Chemistry and Chemical Biology Cornell University  Ithaca New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R117.000582"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnut.2022.1094273"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jlr.2024.100643"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201606069"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.434183"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420\u2010024\u201002224\u20108"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.190290"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s10038\u2010025\u201001379\u20101"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003\u2010021\u201002337\u20101"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.08.008"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/35044114"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C700195200"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.21.5720"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2024.168532"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abo1274"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003\u2010024\u201006164\u2010y"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemphyslip.2020.104971"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.422"},{"key":"e_1_2_8_20_1","doi-asserted-by":"crossref","unstructured":"C. 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