Alumni Professor of Microbiology John E. Cronan at the University of Illinois recently published work on the biotin synthesis pathway and its role in mycobacterium and tuberculosis. Cronan’s lab primarily works on lipid metabolism and fatty acid synthesis. In his recent publication, Cronan takes a deeper dive into the role of biotin in the growth of mycobacteria.
The water-soluble B vitamin cofactor plays an essential role in the establishment of Mycobacterium tuberculosis in the chronic infection of tuberculosis (TB) in murine models. An infectious disease that primarily affects the lungs, TB has fatal health consequences and was once one of the leading causes of death in the United States. While prevalence of the disease has significantly decreased since the first outbreaks, many current strains of Mycobacterium tuberculosis are resistant to previously effective tuberculosis drugs. The need to identify novel drug targets is extremely important, given the rise in deaths caused by this pathogen.
Biotin poses as an excellent therapeutic target because biosynthesis of the cofactor is required for mycobacterial growth, and the subsequent establishment of the pathogen to maintain chronic infection of TB in vivo. Additionally, regulation of the biotin synthesis pathway holds great potential because mammals are unable to synthesize the vitamin, thus inhibitors of the pathway would likely not interact or cause downstream effects on the host. Despite this, there are many gaps in our knowledge of the mycobacterial biotin synthetic pathway. The mechanism of synthesis of the pimelic acid moiety, for example, that contributes to most biotin carbon atoms, is unknown. Cronan and his lab worked to bridge these gaps in “The primary step of biotin synthesis in mycobacteria,” which was recently published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) journal.
Cronan and his lab discovered that the Mycobacterium smegmatis Tam protein plays a key role in the synthesis of the biotin pimelate moiety through methylation of a free carboxyl on the intermediate malonyl-ACP (acyl carrier protein). They found that the expression of Escherichia coli BioC, a methyltransferase involved in the early steps of biotin biosynthesis, allows for growth of M smegmatis biotin auxotroph, which further supports the proposed physiological role of M smegmatis Tam in the biotin synthesis pathway.
Due to biosafety concerns for the severe pathogenicity of M tuberculosis, the Cronan lab was unable to grow the pathogen for future experiments, however, they are continuing their work with biotin. The lab is currently conducting research on biotin ligases and studying deficiencies in binding of the protein. In the future, Cronan hopes to study biotin metabolism in Clostridium difficile, a highly virulent pathogen that affects the colon.
