title: Exploring the Plasmodium falciparum cyclic-adenosine monophosphate (cAMP)-dependent protein kinase (PfPKA) as a therapeutic target.
abstract: One of the prototype mammalian kinases is PKA and various roles have been defined for PKA in malaria pathogenesis. The recently described phospho-proteomes of Plasmodium falciparum introduced a great volume of phospho-peptide data for both basic research and identification of new anti-malaria therapeutic targets. We discuss the importance of phosphorylations detected in vivo at different sites in the parasite R and C subunits of PKA and highlight the inhibitor sites in the parasite R subunit. The N-terminus of the parasite R subunit is predicted to be very flexible and we propose that phosphorylation at multiple sites in this region likely represent docking sites for interactions with other proteins, such as 14-3-3. The most significant observation when the P. falciparum C subunit is compared to mammalian C isoforms is lack of phosphorylation at a key site tail implying that parasite kinase activity is not regulated so tightly as mammalian PKA. Phosphorylation at sites in the activation loop could be mediating a number of processes from regulating parasite kinase activity, to mediating docking of other proteins. The important differences between Plasmodium and mammalian PKA isoforms that indicate the parasite kinase is a valid anti-malaria therapeutic target.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California-San Diego, La Jolla, CA 92093-0687, USA.
authors.forename: Nina M
authors.initials: NM
authors.lastname: Haste
authors.forename: Hana
authors.initials: H
authors.lastname: Talabani
authors.forename: Alex
authors.initials: A
authors.lastname: Doo
authors.forename: Anais
authors.initials: A
authors.lastname: Merckx
authors.forename: Gordon
authors.initials: G
authors.lastname: Langsley
authors.forename: Susan S
authors.initials: SS
authors.lastname: Taylor
mesh_terms: D000962:Antimalarials / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D010766:Phosphorylation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011499:Protein Processing, Post-Translational; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D017868:Cyclic AMP-Dependent Protein Kinases