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Inhibition of SufS in the SUF system by\n D<\/jats:sc>\n \u2010cycloserine (DCS) in\n Plasmodium\u2009falciparum<\/jats:italic>\n apicoplast has recently been reported, indicating that SufS could be a target for malaria therapeutics. However, the mechanistic details underlying the inhibition of SufS by DCS have not yet been clarified. Moreover, inhibition of SufS by the other enantiomer,\n L<\/jats:sc>\n \u2010cycloserine (LCS), has not been investigated. Herein, we investigated the structure\u2010based inhibition mechanisms of SufS by DCS and LCS using\n Bacillus\u2009subtilis<\/jats:italic>\n SufS, whose catalytic mechanism has been well characterized in comparison to that of the\n P<\/jats:italic>\n .\u2009\n falciparum<\/jats:italic>\n SufS. Surprisingly, DCS\u2010 and LCS\u2010mediated inhibitions of SufS occur via distinct mechanisms resulting in pyridoxamine\u20105\u2032\u2010phosphate (PMP) in DCS\u2010mediated inhibition and PMP\u20103\u2010hydroxyisoxazole adduct (PMP\u2010isoxazole) in LCS\u2010mediated inhibition. Biochemical and structural evaluation of SufS variants identified conserved His and Arg residues at the active site as the key determinants of the distinct inhibition mechanisms. The importance of structural elements involved in DCS and LCS\u2010mediated inhibitions of SufS provides valuable insights for the structure\u2010based design of new drugs targeting SufS.\n <\/jats:p>\n <\/jats:sec>\n \n Database<\/jats:title>\n \n Structural data are available in PDB database under the accession numbers\n 6KFY<\/jats:ext-link>\n ,\n 7CEO<\/jats:ext-link>\n ,\n 7CEP<\/jats:ext-link>\n ,\n 7CEQ<\/jats:ext-link>\n ,\n 7CER<\/jats:ext-link>\n ,\n 7CES<\/jats:ext-link>\n ,\n 7CET<\/jats:ext-link>\n ,\n 7CEU<\/jats:ext-link>\n ,\n 7E6A<\/jats:ext-link>\n ,\n 7E6B<\/jats:ext-link>\n ,\n 7E6C<\/jats:ext-link>\n ,\n 7E6D<\/jats:ext-link>\n ,\n 7E6E<\/jats:ext-link>\n , and\n 7E6F<\/jats:ext-link>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/febs.16455","type":"journal-article","created":{"date-parts":[[2022,4,8]],"date-time":"2022-04-08T17:01:15Z","timestamp":1649437275000},"page":"5947-5970","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Cycloserine enantiomers inhibit PLP\u2010dependent cysteine desulfurase SufS via distinct mechanisms"],"prefix":"10.1111","volume":"289","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4661-840X","authenticated-orcid":false,"given":"Ryosuke","family":"Nakamura","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Graduate School of Science and Engineering Saitama University Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1409-3784","authenticated-orcid":false,"given":"Shoko","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology 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