Exploration of the control of Plasmodium falciparum intraerythrocytic growth and development is in its infancy. Understanding the signals and effectors of parasite progression will enhance our knowledge of how this parasite survives in its host cell and will uncover new targets for chemotherapy. PfHO-1 is a heme oxygenase-like protein of unknown function expressed in intraerythrocytic malaria parasites. We have found that PfHO-1 has a porphyrin-responsive DNA- binding activity and associates preferentially with genes that are involved in protein synthesis. Our hypothesis is that PfHO-1 responds to heme accumulation from hemoglobin degradation and is crucial for intra-erythrocytic P. falciparum development. The goal of the study proposed here is to test this hypothesis. We will assess the response of PfHO-1 to perturbation of intracellular porphyrin levels in intraerythrocytic P. falciparum and in an E. coli reporter system. We will impair PfHO-1 action by a new double-positive selection gene knockout approach and by conditional expression of a porphyrin-unresponsive version of the protein. These studies will allow us to establish whether PfHO-1 plays an important role in sensing cellular porphyrin levels and participating in critical aspects of cellular homeostasis. The proposed experiments will also develop new technologies for porphyrin manipulation and for selection of deleterious phenotypes in reverse genetically engineered parasites.
Malaria is one of the world's devastating diseases: there are several hundred million cases worldwide and more than one thousand in this country, mostly imported from other countries. We have discovered a malaria parasite protein that responds to heme, a key metabolite for the organism when it is inside human red blood cells. Characterizing the function of this important protein has the potential to spur development of new antimalarial chemotherapy.
|Sigala, Paul A; Morante, Koldo; Tsumoto, Kouhei et al. (2016) In-Cell Enzymology To Probe His-Heme Ligation in Heme Oxygenase Catalysis. Biochemistry 55:4836-49|
|Sigala, Paul A; Crowley, Jan R; Henderson, Jeffrey P et al. (2015) Deconvoluting heme biosynthesis to target blood-stage malaria parasites. Elife 4:|