RESEARCH Summary
At the University of Maryland, Dr. Hamza deliberately set out to uncover heme trafficking pathways in eukaryotes - which were unknown at the time. His pioneering work with the invertebrate animal model C. elegans has demonstrated that this roundworm is exceptional because it does not synthesize heme but rather utilizes environmental heme to manufacture heme-containing proteins, which have human homologs. This broke the existing paradigm that heme synthesis occurred in all free-living eukaryotes [PNAS 2005]. Using the worm model, we identified the first eukaryotic heme importer/transporter (HRG-1) which is conserved in zebrafish and humans [Nature 2008]. We uncovered how heme is exported from the intestine to other tissues including the embryos by HRG-3 and ABCC5/MRP5 [Cell 2011; Cell Metabolism 2014], and more recently how organs communicate to each other to maintain organismal heme homeostasis by HRG-7 [Nature Cell Biology 2017]. These findings represent major discoveries in heme trafficking and establish a heuristic paradigm for heme transport in animals. Beyond C. elegans, we have shown that related free-living and parasitic nematodes (helminths) do not synthesize heme, much like Trypanosomes and Leishmania. Thus, selective targeting of parasite heme transport pathways could be their Achilles heel. Our groundbreaking studies resulted not only in the identification of homologs for heme transporters in humans [Cell Metabolism 2013; PNAS 2016a; PNAS 2016b] but also in parasites such as hookworms, filarial worms and Leishmania, which rely on host heme for survival [Infect Immun 2006, PLoS NTD. 2009; PLoS Path. 2012]. We anticipate that our studies will lead to identification of inhibitors that can target heme transport pathway in parasites which infect humans, livestock, and plants, as well as in humans with genetic disorders of heme and iron metabolism.
