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

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 () and Dirk Schnappinger ()
Additional contact information
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

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48448-1

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