{"doi":"10.1021/jacs.3c11402","title":"Uridine Bisphosphonates Differentiate Phosphoglycosyl Transferase Superfamilies","abstract":"Complex bacterial glycoconjugates drive interactions between pathogens, symbionts, and their human hosts. Glycoconjugate biosynthesis is initiated at the membrane interface by phosphoglycosyl transferases (PGTs), which catalyze the transfer of a phosphosugar from a soluble uridine diphosphosugar (UDP-sugar) substrate to a membrane-bound polyprenol-phosphate (Pren-P). The two distinct superfamilies of PGT enzymes (polytopic and monotopic) show striking differences in their structure and mechanism. We designed and synthesized a series of uridine bisphosphonates (UBPs), wherein the diphosphate of the UDP and UDP-sugar is replaced by a substituted methylene bisphosphonate (CXY-BPs; X/Y = F/F, Cl/Cl, ( S )-H/F, ( R )-H/F, H/H, CH 3 /CH 3 ). UBPs and UBPs incorporating an N -acetylglucosamine (GlcNAc) substituent at the β-phosphonate were evaluated as inhibitors of a polytopic PGT (WecA from Thermotoga maritima ) and a monotopic PGT (PglC from Campylobacter jejuni ). Although CHF-BP most closely mimics diphosphate with respect to its acid/base properties, the less basic CF 2 –BP conjugate more strongly inhibited PglC, whereas the more basic CH 2 -BP analogue was the strongest inhibitor of WecA. These surprising differences indicate different modes of ligand binding for the different PGT superfamilies, implicating a modified P–O – interaction with the structural Mg 2+ . For the monoPGT enzyme, the two diastereomeric CHF-BP conjugates, which feature a chiral center at the P α -CHF-P β carbon, also exhibited strikingly different binding affinities and the inclusion of GlcNAc with the native α-anomer configuration significantly improved binding affinity. UBP-sugars are thus revealed as informative new mechanistic probes of PGTs that may aid development of novel antibiotic agents for the exclusively prokaryotic monoPGT superfamily.","journal":"Journal of the American Chemical Society","year":2024,"id":464670,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":452552,"name":"Pouya Haratipour","orcid":"0000-0003-0181-8958","position":1,"is_corresponding":false},{"id":1192004,"name":"Michaela Jacobs","orcid":"0009-0005-6063-5010","position":2,"is_corresponding":false},{"id":1060803,"name":"Hannah M. Bernstein","orcid":"0000-0003-0871-0376","position":3,"is_corresponding":false},{"id":452555,"name":"B. A. Kashemirov","orcid":"0000-0001-7175-9960","position":4,"is_corresponding":false},{"id":452556,"name":"Charles E. McKenna","orcid":"0000-0002-3540-6663","position":5,"is_corresponding":false},{"id":400628,"name":"Barbara Imperiali","orcid":"0000-0002-5749-7869","position":6,"is_corresponding":false},{"id":1192003,"name":"Leah M. Seebald","orcid":"0000-0001-8890-8985","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:04:42.082401Z","pmid":"38271668","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}