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Mass spectrometric techniques are the method of choice for their analysis. However, the broad investigation of this metabolite class remains challenging. Derivatization of carboxylic acids represents a strategy to overcome these limitations but available methods suffer from diverse analytical challenges. Herein, we have designed a novel strategy introducing 4\u2010nitrophenyl\u2010<jats:italic>2H<\/jats:italic>\u2010azirine as a new chemoselective moiety for the first time for carboxylic acid metabolites. This moiety was selected as it rapidly forms a stable amide bond and also generates a new ketone, which can be analyzed by our recently developed <jats:italic>quant\u2010<\/jats:italic>SCHEMA method specific for carbonyl metabolites. Optimization of this new method revealed a high reproducibility and robustness, which was utilized to validate 102\u2005metabolic carboxylic acids using authentic synthetic standard conjugates in human plasma samples including nine metabolites that were newly detected. Using this sequential analysis of the carbonyl\u2010 and carboxylic acid\u2010metabolomes revealed alterations of the ketogenesis pathway, which demonstrates the vast benefit of our unique methodology. We anticipate that the developed azirine moiety with rapid functional group transformation will find broad application in diverse chemical biology research fields.<\/jats:p>","DOI":"10.1002\/anie.202318579","type":"journal-article","created":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T05:50:09Z","timestamp":1705557009000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Rapid and Bifunctional Chemoselective Metabolome Analysis of Liver Disease Plasma Using the Reagent 4\u2010Nitrophenyl\u20102<i>H<\/i>\u2010azirine"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8330-7072","authenticated-orcid":false,"given":"Weifeng","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Chemistry\u2014 BMC Science for Life Laboratory Uppsala University  Box\u2005576 SE-75123 Uppsala 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