Phosphagen Kinase System of the Trematode Paragonimus westermani: Cloning and Expression of a Novel Chemotherapeutic Target

Abstract

Paragonimiasis is a food-borne trematode infection that affects 22 million people in at least 20 countries (World Health Organization [WHO], 2002) with 293 million more at risk of infection (Keiser & Utzinger, 2007). In East, Southeast, and South Asia, pulmonary paragonimiasis is commonly caused by the trematode Paragonimus westermani (Blair et al., 2007). Humans get infected by this lung fluke by ingesting metacercariae present in raw freshwater crabs or by eating raw meat of paratenic hosts such as omnivorous mammals (Miyazaki & Habe, 1976). Human paragonimiasis has been reported to be re-emerging in previously endemic areas in Japan (Mukae et al., 2001; Nakano et al., 2001, and Kirino et al., 2009) and increasing in some regions of China (Lieu et al., 2008). New foci of transmission have also been reported in Lao PDR (Odermatt et al., 2009). Currently, either praziquantel or triclabendazole is effective for the treatment of pulmonary paragonimiasis. However, since these are the only viable drugs against this infection, there is a need to develop back up drugs while drug resistance is not yet emerging (Keiser & Utzinger, 2007). In addition, a more specific and sensitive detection tool is needed for diagnosing pulmonary paragonimiasis since a considerable number of cases are misdiagnosed as tuberculosis or vice versa due to similarity of some signs and symptoms (WHO, 2002). The rapid availability of parasite genomic sequences coupled with development of robust bioinformatics tools have resulted in the identification of numerous potential drug targets. These include the phosphagen kinases (PKs) that catalyze the reversible transfer of a phosphate between ATP and naturally occurring guanidino substrates. These enzymes play a key role in maintaining cellular energy homeostasis through temporal energy buffering that stabilizes the cellular ATP/ADP hydrolysis (Ellington, 2001). Studies on PKs of parasitic protozoans and nematodes have shown that PKs are important in energy metabolism and adaptation to stress conditions (Platzer et al, 1999; Alonso et al., 2001; Miranda et al., 2006; Pereira et al., 2003; Pereira et al., 2002). Enzyme activity of PK in Trypanosoma cruzi, the causative agent of Chagas disease, has been shown to be inhibited by various compounds such as catechin gallate (Paveto et al., 2004) and arginine analogs