The design and synthesis of inhibitors of dethiobiotin synthetase as potential herbicides

A. R. Rendina*, W. S. Taylor, K. Gibson, G. Lorimer, D. Rayner, B. Lockett, K. Kranis, B. Wexler, D. Marcovici-Mizrahi, A. Nudelman, A. Nudelman, E. Marsilii, H. Chi, Z. Wawrzak, J. Calabrese, W. Huang, J. Jia, G. Schneider, Y. Lindqvist, G. Yang

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    21 Scopus citations


    Dethiobiotin synthetase (DTBS; E.C., the penultimate enzyme in the biosynthesis of the essential vitamin biotin, is a new potential target for novel herbicides. Inhibitors were designed based on mechanistic and structural information. The in-vitro activities of these potential inhibitors versus the bacterial enzyme are reported here. Mimics of 7,8- diaminopelargonic acid (DAPA) or the DAPA carbamate reaction intermediate were substrates or partial substrates for the enzyme. Synergistic binding with ATP was noted with compounds which contained an amino functionality. NMR studies and X-ray structures confirmed that the inhibitors could be phosphorylated by the enzyme. Several series of potential inhibitors were designed to take advantage of this partial substrate activity by generating potentially more tightly bound phosphorylated inhibitors in situ. Structure- activity relationships for these series based on both substrate and inhibitory activity are described herein. An X-ray structure for one of these inhibitors is also discussed. Although considerable potential for inhibitors of this type was demonstrated, none of the compounds reported showed sufficient herbicidal activity to be a commercial proposition.

    Original languageEnglish (US)
    Pages (from-to)236-247
    Number of pages12
    JournalPesticide Science
    Issue number3
    StatePublished - 1999


    • Biotin biosynthesis
    • DAPA
    • DAPA carbamate
    • DTBS
    • Dethiobiotin synthetase
    • Diacid
    • Diamine
    • Diaminopelargonic acid
    • Herbicide
    • Inhibition
    • Phosphate
    • Phosphinate
    • Phosphonate

    ASJC Scopus subject areas

    • Applied Microbiology and Biotechnology


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