Iron–Sulfur Cluster Enzymes of the Methylerythritol Phosphate Pathway: IspG and IspH

Iron-sulfur cluster (Fe-S) enzymes catalyze important biological processes in cellular metabolism. They evolved in the preoxic world and are oxygen sensitive; biology has therefore evolved a range of mechanisms to protect them from oxidative damage. The 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway for isoprenoid biosynthesis has two Fe-S enzymes: IspG and IspH. Both enzymes utilize 3:1 site-differentiated [4Fe-4S] clusters to perform rather unique dehydroxylation reactions. They may play roles in facilitating oxidative stress sensing and signaling. While bacterial IspG and IspH are well characterized, plant IspG and IspH are not. A particularly fascinating aspect of these enzymes is their ability to balance both their biosynthetic catalytic roles and their presumptive signaling roles in metabolism. Here we review current knowledge about the mechanism, structures, and function of IspG and IspH, and we propose future research directions to help answer the many remaining questions about them. We also provide a primer for investigators keen to start working with these enzymes, as they share with the Fe-S family a set of unique handling and experimental challenges.