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penicillin and cephalosporin antibiotics involves the oxidation of the tripeptide \u03b4-(\n                    <jats:sc>l<\/jats:sc>\n                    -\u03b1-aminoadipoyl)-\n                    <jats:sc>l<\/jats:sc>\n                    -cysteinyl-\n                    <jats:sc>d<\/jats:sc>\n                    -valine (ACV) to give the conformationally strained bicyclic penicillin ring system, as catalysed by the Fe(II)-dependent oxidase isopenicillin N synthase (IPNS). The structures of the precursors for the sequential \u03b2-lactam and thiazolidine ring forming steps in IPNS have remained elusive. Here we studied the reaction of anaerobic IPNS:Fe(II):ACV microcrystals with O\n                    <jats:sub>2<\/jats:sub>\n                    using time-resolved serial femtosecond crystallography and X-ray emission spectroscopy. High-resolution structures reveal that ACV cysteinyl oxidation produces a thioaldehyde that unexpectedly does not coordinate the iron centre. The use of deuterium-labelled ACV enabled the observation of a monocyclic \u03b2-lactam with restoration of the Fe\u2013S bond. Together with mutagenesis, spectroscopic and computational studies, the results support Fe(IV)-mediated penicillin formation involving active-site water molecules. These findings provide structural insight into IPNS catalysis, inform on the wider Fe(II) oxygenase superfamily and highlight the power of X-ray free-electron laser methods for resolving transient enzymatic intermediates.\n                  <\/jats:p>","DOI":"10.1038\/s41929-026-01618-4","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T09:02:20Z","timestamp":1791536540000},"page":"1141-1157","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unanticipated intermediates during isopenicillin N synthase catalysis identified by time-resolved X-ray free-electron laser studies"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3448-9559","authenticated-orcid":false,"given":"Patrick","family":"Rabe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4968-914X","authenticated-orcid":false,"given":"Hiroki","family":"Makita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Southwart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6298-7061","authenticated-orcid":false,"given":"Midhun George","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihails","family":"Kazaks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4653-8661","authenticated-orcid":false,"given":"Shyam","family":"Basak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiankun","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5935-9112","authenticated-orcid":false,"given":"William K.","family":"Myers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7289-3544","authenticated-orcid":false,"given":"Margaret D.","family":"Doyle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2859-4475","authenticated-orcid":false,"given":"Philipp S.","family":"Simon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shusaku","family":"Hayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6473-2743","authenticated-orcid":false,"given":"J. 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Nature 401, 721\u2013724 https:\/\/doi.org\/10.1038\/44400 (1999).","journal-title":"Nature"},{"key":"1618_CR9","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1038\/375700a0","volume":"375","author":"PL Roach","year":"1995","unstructured":"Roach, P. L. et al. Crystal structure of isopenicillin N synthase is the first from a new structural family of enzymes. Nature 375, 700\u2013704 https:\/\/doi.org\/10.1038\/375700a0 (1995).","journal-title":"Nature"},{"key":"1618_CR10","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1038\/42990","volume":"387","author":"PL Roach","year":"1997","unstructured":"Roach, P. L. et al. Structure of isopenicillin N synthase complexed with substrate and the mechanism ofpenicillin formation. 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