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This oxygen\u2010sensitive enzyme mediates the reductive dehydroxylation of 2\u2010\n                    <jats:italic>C<\/jats:italic>\n                    \u2010methyl\u2010\n                    <jats:sc>d<\/jats:sc>\n                    \u2010erythritol 2,4\u2010cyclodiphosphate (MEcPP) to (\n                    <jats:italic>E<\/jats:italic>\n                    )\u20104\u2010hydroxy\u20103\u2010methylbut\u20102\u2010en\u20101\u2010yl diphosphate (HMBPP), requiring electron transfer proteins to deliver two electrons needed for catalysis. To probe the mechanism of IspG and access new mechanism\u2010based inhibitors, we synthesized a substrate analogue, monofluoromethyl\u2010\n                    <jats:sc>d<\/jats:sc>\n                    \u2010erythritol cyclodiphosphate, in which the natural methyl group of MEcPP is replaced by a CH\n                    <jats:sub>2<\/jats:sub>\n                    F group. This analogue proved to be a potent inhibitor of IspG. This study also demonstrates that electron capture is a prerequisite for inhibition and that the inhibitor leads to fluoride release in the IspG\u2010catalyzed reaction. Together, these results provide further support for the involvement of a carbanionic intermediate in the IspG mechanism.\n                  <\/jats:p>","DOI":"10.1002\/chem.202502471","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T07:45:04Z","timestamp":1761119104000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Substitution of CH\n                    <sub>3<\/sub>\n                    by CH\n                    <sub>2<\/sub>\n                    F in 2\u2010Methylerythritol Cyclodiphosphate Triggers Potent Inhibition of IspG with Concomitant Fluoride Ion Expulsion"],"prefix":"10.1002","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4922-0402","authenticated-orcid":false,"given":"Clea","family":"Witjaksono","sequence":"first","affiliation":[{"name":"Equipe Chimie Biologique et Applications Th\u00e9rapeutiques Institut de Chimie de Strasbourg UMR 7177 Universit\u00e9 de Strasbourg\/CNRS  4, rue Blaise Pascal Strasbourg 67070 France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0253-9643","authenticated-orcid":false,"given":"Vivien","family":"Herrscher","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Reims Champagne\u2010Ardenne CNRS ICMR  Reims 51100 France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0715-8751","authenticated-orcid":false,"given":"Hannah","family":"Jobelius","sequence":"additional","affiliation":[{"name":"Equipe Chimie Biologique et Applications Th\u00e9rapeutiques Institut de Chimie de Strasbourg UMR 7177 Universit\u00e9 de Strasbourg\/CNRS  4, rue Blaise Pascal Strasbourg 67070 France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathan","family":"No\u00ebl","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Reims Champagne\u2010Ardenne CNRS ICMR  Reims 51100 France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1400-6804","authenticated-orcid":false,"given":"Fabien","family":"Massicot","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Reims Champagne\u2010Ardenne CNRS ICMR  Reims 51100 France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0802-1095","authenticated-orcid":false,"given":"Jean\u2010Luc","family":"Vasse","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Reims Champagne\u2010Ardenne CNRS ICMR  Reims 51100 France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8998-8806","authenticated-orcid":false,"given":"Jean\u2010Bernard","family":"Behr","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Reims Champagne\u2010Ardenne CNRS ICMR  Reims 51100 France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2615-1574","authenticated-orcid":false,"given":"Myriam","family":"Seemann","sequence":"additional","affiliation":[{"name":"Equipe Chimie Biologique et Applications Th\u00e9rapeutiques Institut de Chimie de Strasbourg UMR 7177 Universit\u00e9 de Strasbourg\/CNRS  4, rue Blaise Pascal Strasbourg 67070 France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"volume-title":"2024: Bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance","year":"2024","author":"WHO Bacterial Priority Pathogens List","key":"e_1_2_8_1_1"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02724-0"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)01867-1"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41570-021-00313-1"},{"key":"e_1_2_8_5_1","first-page":"154","volume":"5","author":"Rohmer M.","year":"2004","journal-title":"Curr. 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