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Pathogens, including fungi, parasites, and bacteria, depend on UGP for the synthesis of virulence factors; in particular, various bacterial species utilize UDP-Glc and its derivatives for the synthesis of lipopolysaccharides, capsular polysaccharides, and biofilm exopolysaccharides. UGPs have, therefore, gained attention as anti-bacterial drug target candidates, prompting us to study their structure-function relationships to provide a basis for the rational development of specific inhibitors. UGP function is tied to its oligomeric state, and the majority of bacterial homologs have been described as tetramers encoded by the\n                      <jats:italic>galU<\/jats:italic>\n                      gene. Uniquely, enterobacterial species harbor a second gene,\n                      <jats:italic>galF<\/jats:italic>\n                      , encoding a protein with high homology to UGP, whose function is somewhat controversial. Here, we show that the\n                      <jats:italic>galF<\/jats:italic>\n                      gene of the opportunistic pathogen\n                      <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                      encodes a dimeric protein that has lost UGP activity, likely due to a combination of active site mutations and an inability to tetramerize, whereas the functional\n                      <jats:italic>K. pneumoniae<\/jats:italic>\n                      UGP, encoded by\n                      <jats:italic>galU<\/jats:italic>\n                      , is an active tetramer. Our AlphaFold-assisted structure-function relationship studies underline that tetramerization is essential for bacterial UGP function and is facilitated by a common mechanism utilizing conserved key residues. Targeting the respective molecular interfaces, which are absent in human UGP, could provide a means of selectively inhibiting the bacterial virulence factor UGP and potentially rendering pathogenic species avirulent.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        The enzyme uridine diphosphate-glucose pyrophosphorylase (UGP) is important for the virulence of bacterial pathogens and, therefore, a potential drug target. In this study, we identify the gene encoding the functional UGP in\n                        <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                        , a bacterium notoriously causing severe antibiotic-resistant infections in humans, and reveal structural and functional features that may aid in the development of new antibiotics.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.02071-24","type":"journal-article","created":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T09:00:31Z","timestamp":1734685231000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":8,"title":["Identification and characterization of the functional tetrameric UDP-glucose pyrophosphorylase from\n                    <i>Klebsiella pneumoniae<\/i>"],"prefix":"10.1128","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2768-9736","authenticated-orcid":false,"given":"Isabel","family":"Ram\u00f3n Roth","sequence":"first","affiliation":[{"name":"Institute of Clinical Biochemistry, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0908-6621","authenticated-orcid":false,"given":"Pavel","family":"Kats","sequence":"additional","affiliation":[{"name":"Institute for Biophysical Chemistry, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2021-7296","authenticated-orcid":true,"given":"Timm","family":"Fiebig","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7163-0590","authenticated-orcid":true,"given":"Fran\u00e7oise","family":"Routier","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5240-4205","authenticated-orcid":false,"given":"Roman","family":"Fedorov","sequence":"additional","affiliation":[{"name":"Institute for Biophysical Chemistry, Hannover Medical School","place":["Hannover, Germany"]},{"name":"Division for Structural Biochemistry, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5794-266X","authenticated-orcid":false,"given":"Larissa","family":"Dirr","sequence":"additional","affiliation":[{"name":"Institute for Biomedicine and Glycomics, Griffith University, Gold Coast","place":["Southport, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7174-0442","authenticated-orcid":true,"given":"Jana I.","family":"F\u00fchring","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry, Hannover Medical School","place":["Hannover, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.00539"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/533452"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01019-15"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.11.4.589"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.00078-15"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.4161\/viru.22718"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2023.08.005"},{"key":"e_1_3_3_9_2","unstructured":"Centers for Disease Control and Prevention CDC. 2024. 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