Steroidal antibiotics are antimetabolites of Acanthamoeba steroidogenesis with phylogenetic implications.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 0376606 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1539-7262 (Electronic) Linking ISSN: 00222275 NLM ISO Abbreviation: J Lipid Res Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York] : Elsevier
      Original Publication: Memphis, Lipid Research, inc.
    • Subject Terms:
      Phylogeny*; Acanthamoeba/*drug effects ; Anti-Bacterial Agents/*pharmacology ; Antimetabolites/*pharmacology ; Antiparasitic Agents/*pharmacology ; Sterols/*metabolism ; Sterols/*pharmacology; Acanthamoeba/genetics ; Acanthamoeba/metabolism ; Anti-Bacterial Agents/chemistry ; Antimetabolites/chemistry ; Antiparasitic Agents/chemistry ; Cell Line ; Humans ; Kinetics ; Mutagenesis, Site-Directed ; Parasitic Sensitivity Tests ; Proteomics ; Sterols/chemistry
    • Abstract:
      Pathogenic organisms may be sensitive to inhibitors of sterol biosynthesis, which carry antimetabolite properties, through manipulation of the key enzyme, sterol methyltransferase (SMT). Here, we isolated natural suicide substrates of the ergosterol biosynthesis pathway, cholesta-5,7,22,24-tetraenol (CHT) and ergosta-5,7,22,24(28)-tetraenol (ERGT), and demonstrated their interference in Acanthamoeba castellanii steroidogenesis: CHT and ERGT inhibit trophozoite growth (EC 50 of 51 nM) without affecting cultured human cell growth. Washout experiments confirmed that the target for vulnerability was SMT. Chemical, kinetic, and protein-binding studies of inhibitors assayed with 24- Ac SMT [catalyzing C 28 -sterol via Δ 24(28) -olefin production] and 28- Ac SMT [catalyzing C 29 -sterol via Δ 25(27) -olefin production] revealed interrupted partitioning and irreversible complex formation from the conjugated double bond system in the side chain of either analog, particularly with 28- Ac SMT. Replacement of active site Tyr62 with Phe or Leu residues involved in cation-π interactions that model product specificity prevented protein inactivation. The alkylating properties and high selective index of 10 3 for CHT and ERGT against 28- Ac SMT are indicative of a new class of steroidal antibiotic that, as an antimetabolite, can limit sterol expansion across phylogeny and provide a novel scaffold in the design of amoebicidal drugs. Animal studies of these suicide substrates can further explore the potential of their antibiotic properties.
      (Copyright © 2019 Zhou et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.)
    • Comments:
      Comment in: J Lipid Res. 2019 May;60(5):919-921. (PMID: 30918064)
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    • Grant Information:
      R21 AI119782 United States AI NIAID NIH HHS; R33 AI119782 United States AI NIAID NIH HHS
    • Contributed Indexing:
      Keywords: anti-amoeba drugs; sterol biosynthesis; suicide substrate
    • Accession Number:
      0 (Anti-Bacterial Agents)
      0 (Antimetabolites)
      0 (Antiparasitic Agents)
      0 (Sterols)
    • Publication Date:
      Date Created: 20190203 Date Completed: 20200813 Latest Revision: 20240229
    • Publication Date:
      20240229
    • Accession Number:
      PMC6495176
    • Accession Number:
      10.1194/jlr.M091587
    • Accession Number:
      30709898