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The tetrahydrofolate pathway is involved in several one-carbon fixation pathways. To study such pathways, stable isotope-labelled tracer analysis performed with mass spectrometry is state of the art. However, no such method is currently available for tetrahydrofolate vitamers. In the present work, we established a fit-for-purpose extraction method for the methylotrophic yeast <jats:italic>Komagataella phaffii<\/jats:italic> that allows access to intracellular methyl- and methenyl-tetrahydrofolate (THF) with demonstrated stability over several hours. To determine isotopologue distributions of methyl-THF, LC-QTOFMS provides a selective fragment ion with suitable intensity of at least two isotopologues in all samples, but not for methenyl-THF. However, the addition of ion mobility separation provided a critical selectivity improvement allowing accurate isotopologue distribution analysis of methenyl-THF with LC-IM-TOFMS. Application of these new methods for <jats:sup>13<\/jats:sup>C-tracer experiments revealed a decrease from 83\u2009\u00b1\u20094 to 64\u2009\u00b1\u20095% in the M\u2009+\u20090 carbon isotopologue fraction in methyl-THF after 1\u00a0h of labelling with formate, and to 54\u2009\u00b1\u20095% with methanol. The M\u2009+\u20090 carbon isotopologue fraction of methenyl-THF was reduced from 83\u2009\u00b1\u20092 to 78\u2009\u00b1\u20091% over the same time when using <jats:sup>13<\/jats:sup>C-methanol labelling. The labelling results of multiple strains evidenced the involvement of the THF pathway in the oxygen-tolerant reductive glycine pathway, the presence of the in vivo reduction of formate to formaldehyde, and the activity of the spontaneous condensation reaction of formaldehyde with THF in <jats:italic>K. phaffii<\/jats:italic>.<\/jats:p>","DOI":"10.1007\/s00216-023-04786-5","type":"journal-article","created":{"date-parts":[[2023,6,22]],"date-time":"2023-06-22T10:14:52Z","timestamp":1687428892000},"page":"5151-5163","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Tailored extraction and ion mobility-mass spectrometry enables isotopologue analysis of tetrahydrofolate vitamers"],"prefix":"10.1007","volume":"415","author":[{"given":"Bernd M.","family":"Mitic","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diethard","family":"Mattanovich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Hann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Causon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,6,22]]},"reference":[{"key":"4786_CR1","doi-asserted-by":"publisher","unstructured":"de Vasconcelos BR, Lavoie JM. 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