title: Structural Investigation of Park's Nucleotide on Bacterial Translocase MraY: Discovery of Unexpected MraY Inhibitors.
abstract: Systematic structural modifications of the muramic acid, peptide, and nucleotide moieties of Park's nucleotide were performed to investigate the substrate specificity of B. subtilis MraY (MraYBS). It was found that the simplest analogue of Park's nucleotide only bearing the first two amino acids, l-alanine-iso-d-glutamic acid, could function as a MraYBS substrate. Also, the acid group attached to the Cα of iso-d-glutamic acid was found to play an important role for substrate activity. Epimerization of the C4-hydroxyl group of muramic acid and modification at the 5-position of the uracil in Park's nucleotide were both found to dramatically impair their substrate activity. Unexpectedly, structural modifications on the uracil moiety changed the parent molecule from a substrate to an inhibitor, blocking the MraYBS translocation. One unoptimized inhibitor was found to have a Ki value of 4 ± 1 μM against MraYBS, more potent than tunicamycins.
authors.affiliation: Genomics Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nankang District, Taipei, 11529, Taiwan.
authors.forename: Kuo-Ting
authors.initials: KT
authors.lastname: Chen
authors.affiliation: Genomics Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nankang District, Taipei, 11529, Taiwan.
authors.forename: Po-Ting
authors.initials: PT
authors.lastname: Chen
authors.affiliation: Genomics Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nankang District, Taipei, 11529, Taiwan.
authors.forename: Cheng-Kun
authors.initials: CK
authors.lastname: Lin
authors.affiliation: Genomics Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nankang District, Taipei, 11529, Taiwan.
authors.forename: Lin-Ya
authors.initials: LY
authors.lastname: Huang
authors.affiliation: Genomics Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nankang District, Taipei, 11529, Taiwan.
authors.forename: Chia-Ming
authors.initials: CM
authors.lastname: Hu
authors.affiliation: Genomics Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nankang District, Taipei, 11529, Taiwan.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Chang
authors.affiliation: Genomics Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nankang District, Taipei, 11529, Taiwan.
authors.forename: Hua-Ting
authors.initials: HT
authors.lastname: Hsu
authors.affiliation: Genomics Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nankang District, Taipei, 11529, Taiwan.
authors.forename: Ting-Jen R
authors.initials: TJ
authors.lastname: Cheng
authors.affiliation: Genomics Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nankang District, Taipei, 11529, Taiwan.
authors.forename: Ying-Ta
authors.initials: YT
authors.lastname: Wu
authors.affiliation: Genomics Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nankang District, Taipei, 11529, Taiwan.
authors.forename: Wei-Chieh
authors.initials: WC
authors.lastname: Cheng
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D009690:Nucleic Acid Conformation; D009711:Nucleotides / Q000737:chemistry / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000187:drug effects; D013379:Substrate Specificity; D014166:Transferases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D017855:Transferases (Other Substituted Phosphate Groups)
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D009711:Nucleotides; D014166:Transferases; D017855:Transferases (Other Substituted Phosphate Groups); C079803:mraY protein, Bacteria