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Mycobacterial biotin synthases require an auxiliary protein to convert dethiobiotin into biotin

Author

Listed:
  • Di Qu

    (Weill Cornell Medicine)

  • Peng Ge

    (University of Minnesota)

  • Laure Botella

    (Weill Cornell Medicine)

  • Sae Woong Park

    (Weill Cornell Medicine)

  • Ha-Na Lee

    (Weill Cornell Medicine)

  • Natalie Thornton

    (Weill Cornell Medicine)

  • James M. Bean

    (Memorial Sloan Kettering Cancer Center)

  • Inna V. Krieger

    (Texas A&M University)

  • James C. Sacchettini

    (Texas A&M University)

  • Sabine Ehrt

    (Weill Cornell Medicine)

  • Courtney C. Aldrich

    (University of Minnesota)

  • Dirk Schnappinger

    (Weill Cornell Medicine)

Abstract

Lipid biosynthesis in the pathogen Mycobacterium tuberculosis depends on biotin for posttranslational modification of key enzymes. However, the mycobacterial biotin synthetic pathway is not fully understood. Here, we show that rv1590, a gene of previously unknown function, is required by M. tuberculosis to synthesize biotin. Chemical–generic interaction experiments mapped the function of rv1590 to the conversion of dethiobiotin to biotin, which is catalyzed by biotin synthases (BioB). Biochemical studies confirmed that in contrast to BioB of Escherichia coli, BioB of M. tuberculosis requires Rv1590 (which we named “biotin synthase auxiliary protein” or BsaP), for activity. We found homologs of bsaP associated with bioB in many actinobacterial genomes, and confirmed that BioB of Mycobacterium smegmatis also requires BsaP. Structural comparisons of BsaP-associated biotin synthases with BsaP-independent biotin synthases suggest that the need for BsaP is determined by the [2Fe–2S] cluster that inserts sulfur into dethiobiotin. Our findings open new opportunities to seek BioB inhibitors to treat infections with M. tuberculosis and other pathogens.

Suggested Citation

  • Di Qu & Peng Ge & Laure Botella & Sae Woong Park & Ha-Na Lee & Natalie Thornton & James M. Bean & Inna V. Krieger & James C. Sacchettini & Sabine Ehrt & Courtney C. Aldrich & Dirk Schnappinger, 2024. "Mycobacterial biotin synthases require an auxiliary protein to convert dethiobiotin into biotin," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48448-1
    DOI: 10.1038/s41467-024-48448-1
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    References listed on IDEAS

    as
    1. Michael A DeJesus & Chaitra Ambadipudi & Richard Baker & Christopher Sassetti & Thomas R Ioerger, 2015. "TRANSIT - A Software Tool for Himar1 TnSeq Analysis," PLOS Computational Biology, Public Library of Science, vol. 11(10), pages 1-17, October.
    2. Simon R. Green & Susan H. Davis & Sebastian Damerow & Curtis A. Engelhart & Michael Mathieson & Beatriz Baragaña & David A. Robinson & Jevgenia Tamjar & Alice Dawson & Fabio K. Tamaki & Kirsteen I. Bu, 2022. "Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
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