Bacterial iron-sulfur cluster-containing enzymes (Fe-S enzymes)

Bacterial iron-sulfur (Fe-S) cluster-containing enzymes are a diverse class of proteins that utilize inorganic clusters of iron and sulfur as essential cofactors for a wide range of biological processes, including electron transfer, catalysis, and environmental sensing (NIH, 2012). These enzymes are critical for bacterial survival, participating in central metabolic pathways such as the tricarboxylic acid (TCA) cycle and the non-mevalonate (MEP) pathway for isoprenoid biosynthesis (Nature, 2021). In the context of drug discovery, specific Fe-S enzymes like IspG and IspH are highly attractive targets because they are essential for many pathogenic bacteria and malaria parasites but are entirely absent in humans, who utilize the mevalonate pathway instead (NIH, 2011). Inhibiting these enzymes not only halts the production of vital isoprenoids but can also lead to the accumulation of metabolites like HMBPP, which potently activates the human innate immune system, specifically Vγ9Vδ2 T cells (Nature, 2021). This dual-acting mechanism makes bacterial Fe-S enzymes promising candidates for the development of novel antibiotics and immuno-therapeutics. However, the high sensitivity of Fe-S clusters to reactive oxygen and nitrogen species, as well as the potential for off-target effects on human Fe-S proteins, presents significant challenges in drug design and safety (NIH, 2017).

Other names

Iron-sulfur proteins[Fe-S] cluster enzymesBacterial Fe-S proteinsBacterial iron-sulfur proteinsIron-sulfur cluster-dependent enzymes

Inhibition of the non-mevalonate (MEP) pathway for isoprenoid biosynthesis; disruption of iron-sulfur cluster stability through oxidative or nitrosative stress; induction of metabolic chaos; and activation of host γδ T-cells via accumulation of the metabolite HMBPP.