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oai:figshare.com:article/34027426 2026-09-29T19:14:33Z category_1 category_4 category_8 category_19 category_21 category_873 category_734 category_64 category_132 portal_63 item_type_6 month_year_09_2026

The Active Component of Dehydrophos Covalently Binds to Acetohydroxyacid Synthase and Inhibits the Growth of Uropathogenic Escherichia coli Xin Lin (149944) Sharon Chow (2162938) Paul Malek Mirzayans (2421247) Jiahui Tng (8879219) Gerhard Schenk (1471624) Craig M. Williams (1939036) Luke W. Guddat (288645) Biophysics Biochemistry Microbiology Pharmacology Biotechnology Chemical Sciences not elsewhere classified Biological Sciences not elsewhere classified Cancer Infectious Diseases uropathogenic escherichia coli chain amino acids cell susceptibility assays 22 å resolution natural product antibiotic crystal structure provides biologically active component also structurally different saccharomyces cerevisiae ahas dehydrophos covalently binds crystal structure binds covalently active component starting point rational design pyruvate analog novel antimicrobial methyl acetylphosphonate drug development developed previously dependent enzymes commercial herbicides antifungal therapeutics antibiotic activity also shown acetohydroxyacid synthase Acetohydroxyacid synthase (AHAS) is the first enzyme in the branched-chain amino acid biosynthesis pathway and is the target for more than 50 commercially deployed herbicides. This enzyme has also been suggested as a target for the discovery of novel antimicrobial and antifungal therapeutics. Dehydrophos, a natural product antibiotic, is a potential new lead inhibitor of AHASs for drug development, whereby the biologically active component is proposed to be methyl acetylphosphonate (MAP). MAP has been suggested as a pyruvate analog that inhibits ThDP-dependent enzymes, including AHAS. Here, the crystal structure of Saccharomyces cerevisiae AHAS in complex with MAP has been determined to 2.22 Å resolution, showing that it binds covalently with ThDP. We have also shown that MAP alone is effective in inhibiting the growth of uropathogenic Escherichia coli (UPEC) in cell susceptibility assays and that this activity is lost when exogenous branched-chain amino acids (BCAAs) are added. This suggests that AHAS is a target for the antibiotic activity of MAP and dehydrophos. Our crystal structure provides a starting point for the rational design of ThDP covalently bound AHAS inhibitors that are also structurally different from those that have been developed previously as commercial herbicides that inhibit AHAS. 2026-09-29T00:00:00Z Text Journal contribution 10.1021/acs.biochem.6c00555.s001 https://figshare.com/articles/journal_contribution/The_Active_Component_of_Dehydrophos_Covalently_Binds_to_Acetohydroxyacid_Synthase_and_Inhibits_the_Growth_of_Uropathogenic_Escherichia_coli/34027426 CC BY-NC 4.0