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Title: LACK OF HEME SYNTHESIS IN A FREE-LIVING EUKARYOTE

Author
item Carta, Lynn
item RAO, A - UNIVERSITY OF MARYLAND
item LESUISSE, E - INSTITUTE JACQUES MONOD
item HAMZA, I - UNIVERSITY OF MARYLAND

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/10/2005
Publication Date: 3/1/2005
Citation: Carta, L.K., Rao, A., Lesuisse, E., Hamza, I. 2005. Lack of heme synthesis in a free-living eukaryote. Proceedings of the National Academy of Sciences 102: 4270-4275.

Interpretive Summary: Parasitic nematodes and other worms are an enormous burden to public health and global agriculture, with more than two billion people infected and an annual crop loss of eighty billion dollars. Iron loss through worm parasites results in anemia, a worldwide public health concern. One problem in worm parasite control is the development of resistance to the few currently available drugs. Therefore, there is a need to find vulnerabilities in roundworm (nematode) and flatworm parasite metabolism of essential nutrients by looking for differences in metabolic pathways that distinguish them from their hosts. These differences may become the focus of new control methods. One such nutrient is iron, but how worms insert iron into a biologically useable form within the heme protein is not known. In this paper, the biochemical pathways known to make the heme protein in other living things were examined in parasitic and non-parasitic worms through the use of biochemical data from genome databases and laboratory studies. Surprisingly, neither the nematodes nor the flatworm, whether parasitic or free-living, could produce their own heme, unlike plants, yeast and most bacteria and animals. The results are significant because they provide the first indication of specific defects in heme biochemistry in these worms and represent a promising target for anti-parasitic drugs. This information will be used by other researchers studying worm parasitism and developing new pharmaceuticals or controls for crop nematodes.

Technical Abstract: In most free-living eukaryotes studied thus far, heme is synthesized from a series of intermediates through a well-defined, evolutionarily conserved pathway. We found that free-living worms, including the model genetic organism Caenorhabditis elegans, and parasitic helminths are unable to synthesize heme de novo, even though these animals contain hemoproteins that function in key biological processes. Radioisotope, fluorescence labeling, and heme analog studies suggest that C. elegans acquires heme from exogenous sources. Iron-deprived worms were unable to grow in the presence of adequate heme unless rescued by increasing heme levels in the growth medium. These data indicate that, although worms utilize dietary heme for incorporation into hemoproteins, ingested heme is also used as an iron source when iron is limiting. Our results provide a biochemical basis for the dependence of worm growth and development on heme, and suggest that pharmacologic targeting of heme transport pathways in worms could be an important control measure for helminthic infections.