Iron-sulfur (Fe-S) clusters are essential and extremely versatile protein co-factors in the metabolism of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. Alongside canonical roles in important cellular processes, Mtb regulatory proteins routinely exploit the redox-sensitive nature of Fe-S clusters to respond quickly to environmental stress signals inside host cells. Moreover, Fe-S clusters have also been linked to latent infection in Mtb, a key roadblock in the treatment of TB. The process of Fe-S cluster biogenesis is still largely unknown in Mtb, where cluster assembly is primarily carried out by proteins of the sulfur mobilisation factor (Suf) pathway. As the Suf system is not utilised in humans, it represents a particularly attractive target in the search for novel anti-TB treatments.
The Suf system comprises a network of proteins that mobilise sulfur and iron, assemble nascent clusters, and then transfer them onto Fe-S proteins. In this process, sulfur, obtained by the cysteine desulfurase (Csd) SufS, and iron are delivered to the SufBCD core complex where Fe-S clusters are assembled. We have determined the crystal structure of Mtb-SufS to 2.0 Å resolution in complex with the pyridoxal phosphate cofactor and L-alanine. This structure provides us with an atomic insight into the desulfuration reaction mechanism. We have also shown that a U-type sulfide transfer protein, encoded by suf operon gene Rv1465, is required for activation of SufS Csd activity. These findings contribute to our understanding of Fe-S cluster biogenesis in Mtb and may provide novel targets for the development of anti-mycobacterial agents.