Chemical genetics takes advantage of small molecule libraries to dissect complex biological processes.  Small molecules can act very fast, can be very specific, and can help to distinguish molecular steps and hierarchical regulation of biological processes. Our laboratory has developed a fluorescence cell-based assay to screen for inhibitors of iron uptake by mammalian cells.  Using this approach, we have discovered several important new small molecule inhibitors to probe different pathways of iron uptake. Our ultimate goal is to use these reagents to advance our understanding of the factors, mechanisms, and regulation of iron uptake.  Iron is an essential nutrient but also a potent toxicant.  Iron deficiency remains the most prevalent nutritional problem worldwide, yet the genetic basis for hereditary hemochromatosis indicates a large portion of the global population is also susceptible to iron overload.  Increased knowledge about transport factors and how they protect against iron deficiency and overload is essential to more broadly address these significant health problems.  In particular, we have characterized the mechanism of action of �ferristatins� to inhibit iron uptake from the serum protein transferrin.  Ferristatins disrupt endocytic uptake of iron through down-regulation of the transferrin receptor both in vivo and in vitro.  In vivo studies show that ferristatin II induces dissociation of the transferrin receptor from the hereditary hemochromatosis factor HFE. Our results demonstrate induction of liver hepcidin synthesis, reduced serum iron levels, and lower intestinal iron uptake in treated animals as a consequence of the small molecule's activity.  In vitro use of ferristatins has revealed a novel lipid raft membrane trafficking pathway for the transferrin receptor that mediates its degradation under these conditions.  Such studies underscore the utility of small molecules to shed molecular insights into the regulation of iron metabolism.

Chemical genetics of iron transport

245th National Meeting (2013)

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