{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T15:26:59Z","timestamp":1787153219332,"version":"build-2736575974"},"reference-count":27,"publisher":"American Chemical Society (ACS)","issue":"32","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100016755","name":"International Institute for Nanotechnology, Northwestern University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016755","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000148","name":"Division of Electrical, Communications and Cyber Systems","doi-asserted-by":"publisher","award":["2025633"],"award-info":[{"award-number":["2025633"]}],"id":[{"id":"10.13039\/100000148","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100022987","name":"State of Illinois","doi-asserted-by":"publisher","award":["1S10OD012016-01"],"award-info":[{"award-number":["1S10OD012016-01"]}],"id":[{"id":"10.13039\/100022987","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100022987","name":"State of Illinois","doi-asserted-by":"publisher","award":["1S10RR019071-01A1"],"award-info":[{"award-number":["1S10RR019071-01A1"]}],"id":[{"id":"10.13039\/100022987","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 DA018310"],"award-info":[{"award-number":["P30 DA018310"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P41 GM108569"],"award-info":[{"award-number":["P41 GM108569"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA260250"],"award-info":[{"award-number":["R01 CA260250"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 DA030604"],"award-info":[{"award-number":["R01 DA030604"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["1904480"],"award-info":[{"award-number":["1904480"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Human ornithine aminotransferase (hOAT) is a pyridoxal 5\u2032-phosphate (PLP)-dependent enzyme that has been implicated in several cancers due to the essential role in the synthesis of glutamine and proline. Inhibition of hOAT may provide a novel method to treat a variety of cancers. In recent years, selective inhibition of hOAT through mechanism-based inactivation has shown promise in the treatment of hepatocellular carcinoma. Inspired by the recently reported hOAT-selective \u03b4-deprotonation and previously proposed ring-strain mediated mechanisms of inactivation, we designed, synthesized, and evaluated (1S,3R,5R)-3-amino-6,6-difluorobicyclo[3.1.0]hexane-1-carboxylic acid (5), a time-dependent inhibitor of hOAT. Structural and mechanistic studies validated the proposed mechanism of 5, which undergoes a ring-opening mechanism to form a PLP-inactivator adduct that is tightly bound in the active site of hOAT. Intact protein mass spectrometry, 19F NMR spectroscopy, transient-state kinetic studies, X-ray crystallography, and QM calculations were used to determine the final adduct and explore the mechanism of inactivation of 5. This is the first report of a ring-opening event in the active site of hOAT.<\/jats:p>","DOI":"10.1021\/jacs.6c11041","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T19:01:27Z","timestamp":1786042887000},"page":"34916-34927","source":"Crossref","is-referenced-by-count":0,"title":["Design\nand Elucidation of a Strain-Relief-Driven Ring\nOpening Mechanism of Inactivation of Ornithine Aminotransferase by\n(1\n                    <i>S<\/i>\n                    ,3\n                    <i>R<\/i>\n                    ,5\n                    <i>R<\/i>\n                    )-3-Amino-6,6-difluorobicyclo[3.1.0]hexane-1-carboxylic\nAcid"],"prefix":"10.1021","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2816-7120","authenticated-orcid":true,"given":"Allison N.","family":"Devitt","sequence":"first","affiliation":[{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail L.","family":"Vargas","sequence":"additional","affiliation":[{"name":"Loyola University Chicago , , , ,","place":["Chicago, Illinois, United States, 60660"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7942-6850","authenticated-orcid":true,"given":"Cathy Kexin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5480-4192","authenticated-orcid":true,"given":"Benjamin James","family":"Des Soye","sequence":"additional","affiliation":[{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maanasa","family":"Narayanomoorthy","sequence":"additional","affiliation":[{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inna","family":"Sokolenko","sequence":"additional","affiliation":[{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron K.","family":"Origenes","sequence":"additional","affiliation":[{"name":"Loyola University Chicago , , , ,","place":["Chicago, Illinois, United States, 60660"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler B.","family":"Alt","sequence":"additional","affiliation":[{"name":"Loyola University Chicago , , , ,","place":["Chicago, Illinois, United States, 60660"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9859-0787","authenticated-orcid":true,"given":"Pathum M.","family":"Weerawarna","sequence":"additional","affiliation":[{"name":"Indiana University , , , ,","place":["Indianapolis, Indiana, United States, 46202"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6807-1302","authenticated-orcid":true,"given":"Graham R.","family":"Moran","sequence":"additional","affiliation":[{"name":"Loyola University Chicago , , , ,","place":["Chicago, Illinois, United States, 60660"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8815-3372","authenticated-orcid":true,"given":"Neil L.","family":"Kelleher","sequence":"additional","affiliation":[{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7587-703X","authenticated-orcid":true,"given":"Dali","family":"Liu","sequence":"additional","affiliation":[{"name":"Loyola University Chicago , , , ,","place":["Chicago, Illinois, United States, 60660"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9034-1084","authenticated-orcid":true,"given":"Richard B.","family":"Silverman","sequence":"additional","affiliation":[{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Chicago, Illinois, United States, 60611"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"2026081910244741800_cit1","doi-asserted-by":"publisher","DOI":"10.1177\/20503121211067083","article-title":"A recent\ndevelopment of new therapeutic agents and novel drug targets for cancer\ntreatment","volume":"9","author":"Kifle","year":"2021","journal-title":"SAGE Open Med."},{"issue":"4","key":"2026081910244741800_cit2","doi-asserted-by":"publisher","first-page":"429","DOI":"10.2174\/1381612826666200115095937","article-title":"Exploring\nDysregulated Signaling Pathways in Cancer","volume":"26","author":"Nisar","year":"2020","journal-title":"Curr.\nPharm. 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Cell Physiol."},{"issue":"2","key":"2026081910244741800_cit8","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9020107","article-title":"Breast\nCancer-Derived Microvesicles Are the Source\nof Functional Metabolic Enzymes as Potential Targets for Cancer Therapy","volume":"9","author":"Risha","year":"2021","journal-title":"Biomedicines"},{"key":"2026081910244741800_cit9","doi-asserted-by":"publisher","DOI":"10.3389\/pore.2021.1610075","article-title":"Glutamine Metabolism Scoring Predicts\nPrognosis and Therapeutic Resistance\nin Hepatocellular Carcinoma","volume":"27","author":"Ying","year":"2021","journal-title":"Pathol. Oncol.\nRes."},{"issue":"1","key":"2026081910244741800_cit10","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-017-0623-x","article-title":"Regulation\nof stem-like cancer cells by glutamine through \u03b2-catenin pathway\nmediated by redox signaling","volume":"16","author":"Liao","year":"2017","journal-title":"Mol. Cancer"},{"issue":"1","key":"2026081910244741800_cit11","doi-asserted-by":"publisher","DOI":"10.3390\/cells11010140","article-title":"Amino Acid\nMetabolism in Cancer Drug Resistance","volume":"11","author":"Yoo","year":"2022","journal-title":"Cells"},{"key":"2026081910244741800_cit12","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14030553","article-title":"Advancing Cancer Treatment by Targeting Glutamine Metabolism -A Roadmap","volume":"14","author":"Halama","year":"2022","journal-title":"Cancers"},{"issue":"23","key":"2026081910244741800_cit13","doi-asserted-by":"publisher","first-page":"8983","DOI":"10.1073\/pnas.1203244109","article-title":"Reprogramming\nof proline and glutamine metabolism contributes\nto the proliferative and metabolic responses regulated by oncogenic\ntranscription factor c-MYC","volume":"109","author":"Liu","year":"2012","journal-title":"Proc. Natl. Acad.\nSci. U.S.A."},{"issue":"3","key":"2026081910244741800_cit14","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1007\/s00109-011-0731-9","article-title":"Glutamine: pleiotropic\nroles in tumor growth and stress resistance","volume":"89","author":"Shanware","year":"2011","journal-title":"J. Mol. Med."},{"issue":"49","key":"2026081910244741800_cit15","doi-asserted-by":"publisher","first-page":"19345","DOI":"10.1073\/pnas.0709747104","article-title":"Beyond aerobic glycolysis:\nTransformed\ncells can engage in glutamine metabolism that exceeds the requirement\nfor protein and nucleotide synthesis","volume":"104","author":"DeBerardinis","year":"2007","journal-title":"Proc.\nNatl. Acad. Sci. U.S.A."},{"issue":"54","key":"2026081910244741800_cit16","doi-asserted-by":"publisher","first-page":"8293","DOI":"10.1038\/sj.onc.1206118","article-title":"New targets\nof \u03b2-catenin signaling in the liver are involved in the glutamine\nmetabolism","volume":"21","author":"Cadoret","year":"2002","journal-title":"Oncogene"},{"issue":"43","key":"2026081910244741800_cit17","doi-asserted-by":"publisher","first-page":"36409","DOI":"10.1074\/jbc.M506977200","article-title":"Determinants\nof substrate specificity in omega-aminotransferases","volume":"280","author":"Markova","year":"2005","journal-title":"J. Biol. Chem."},{"issue":"12","key":"2026081910244741800_cit18","doi-asserted-by":"publisher","first-page":"5629","DOI":"10.1021\/jacs.2c00924","article-title":"Rational\nDesign, Synthesis, and Mechanism of (3S,4R)-3-Amino-4-(difluoromethyl)cyclopent-1-ene-1-carboxylic\nAcid: Employing a Second-Deprotonation Strategy for Selectivity of\nHuman Ornithine Aminotransferase over GABA Aminotransferase","volume":"144","author":"Zhu","year":"2022","journal-title":"J. Am. Chem. Soc."},{"issue":"5","key":"2026081910244741800_cit19","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1021\/acschembio.4c00022","article-title":"Design,\nSynthesis, and Mechanistic Studies of (R)-3-Amino-5,5-difluorocyclohex-1-ene-1-carboxylic\nAcid as an Inactivator of Human Ornithine Aminotransferase","volume":"19","author":"Devitt","year":"2024","journal-title":"ACS Chem. Biol."},{"issue":"12","key":"2026081910244741800_cit20","doi-asserted-by":"publisher","first-page":"9110","DOI":"10.1021\/acs.joc.4c00781","article-title":"Synthesis\nof (2R,4S)-4-Amino-5-hydroxybicyclo[3.1.1]heptane-2-carboxylic Acid\nvia an Asymmetric Intramolecular Mannich Reaction","volume":"89","author":"Dukes","year":"2024","journal-title":"J. Org. Chem."},{"issue":"48","key":"2026081910244741800_cit21","doi-asserted-by":"publisher","first-page":"14513","DOI":"10.1021\/bi061592m","article-title":"(\u00b1)-(1S,2R,5S)-5-Amino-2-fluorocyclohex-3-enecarboxylic\nacid. A potent GABA aminotransferase inactivator that irreversibly\ninhibits via an elimination-aromatization pathway","volume":"45","author":"Wang","year":"2006","journal-title":"Biochemistry"},{"issue":"1","key":"2026081910244741800_cit22","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1021\/jacs.3c07992","article-title":"Pd\/IPr(BIDEA)-Catalyzed Hydrodefluorination\nof gem-Difluorocyclopropanes:\nRegioselective Synthesis of Terminal Fluoroalkenes","volume":"146","author":"Qian","year":"2024","journal-title":"J. Am. Chem. Soc."},{"issue":"7","key":"2026081910244741800_cit23","doi-asserted-by":"publisher","first-page":"1602","DOI":"10.1021\/acs.orglett.7b00325","article-title":"Regio- and\nStereoselective Synthesis of Functionalized Cyclopentene Derivatives\nvia Mizoroki-Heck Reactions","volume":"19","author":"Wetzel","year":"2017","journal-title":"Org. Lett."},{"issue":"7","key":"2026081910244741800_cit24","doi-asserted-by":"publisher","first-page":"2242","DOI":"10.1016\/j.bmc.2005.11.010","article-title":"Syntheses and evaluation of fluorinated conformationally\nrestricted analogues of GABA as potential inhibitors of GABA aminotransferase","volume":"14","author":"Wang","year":"2006","journal-title":"Bioorg. Med. Chem."},{"issue":"1","key":"2026081910244741800_cit25","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1021\/acschembio.0c00728","article-title":"Structural and Kinetic\nAnalyses Reveal the Dual Inhibition Modes of Ornithine Aminotransferase\nby (1S,3S)-3-Amino-4-(hexafluoropropan-2-ylidenyl)-cyclopentane-1-carboxylic\nAcid (BCF(3))","volume":"16","author":"Butrin","year":"2021","journal-title":"ACS Chem. Biol."},{"issue":"14","key":"2026081910244741800_cit26","doi-asserted-by":"publisher","first-page":"5970","DOI":"10.1074\/jbc.M116.774588","article-title":"Direct evidence\nthat an extended hydrogen-bonding network\ninfluences activation of pyridoxal 5\u2032-phosphate in aspartate\naminotransferase","volume":"292","author":"Dajnowicz","year":"2017","journal-title":"J. Biol. Chem."},{"issue":"6","key":"2026081910244741800_cit27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.101969","article-title":"Determination\nof the pH dependence, substrate specificity, and turnovers of alternative\nsubstrates for human ornithine aminotransferase","volume":"298","author":"Butrin","year":"2022","journal-title":"J. Biol. Chem."}],"container-title":["Journal of the American\nChemical Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jacs.6c11041","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/148\/32\/34916\/66450157\/jacs.6c11041.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/148\/32\/34916\/66450157\/jacs.6c11041.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T14:48:28Z","timestamp":1787150908000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jacsat\/article\/148\/32\/34916\/5249753\/Design-and-Elucidation-of-a-Strain-Relief-Driven"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":27,"journal-issue":{"issue":"32","published-online":{"date-parts":[[2026,8,6]]},"published-print":{"date-parts":[[2026,8,19]]}},"URL":"https:\/\/doi.org\/10.1021\/jacs.6c11041","relation":{},"ISSN":["0002-7863","1520-5126"],"issn-type":[{"value":"0002-7863","type":"print"},{"value":"1520-5126","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,6]]}}}