Cyclic nucleotide-specific phosphodiesterases of Plasmodium falciparum: PfPDE alpha, a non-essential cGMP-specific PDE that is an integral membrane protein

Cyclic nucleotide-specific phosphodiesterases (PDEs) have come into focus as interesting potential targets for PDE inhibitor-based anti-parasitic drugs. Genomes of the various agents Of human malaria, most notably Plasmodium falciparum, all contain four genes for class I PDEs. The catalytic domains of these enzymes are closely related to those of the I I human PDE families. This presents the possibility that the available vast expertise in developing drugs against human PDEs might now also be applied to developing compounds that are active against malarial PDEs. The current study identifies four Plasmodium genes that code for PfPDE alpha, PfPDE beta, PfPDE gamma and PfPDE delta, respectively. It further demonstrates that the PfPDE alpha polypeptide exists in two versions (PfPDE alpha A and PfPDE alpha B) that are generated by alternative splicing of the primary transcript. All malarial PDEs contain several transmembrane helices in their N-terminal regions, indicating that they are integral membrane proteins. In agreement with this prediction, essentially all PDE activity is associated with the cell membranes. PfPDE alpha was characterized as a cGMP-specific PDE that is not sensitive to a number of standard PDE inhibitors. Genetic ablation of the PfPDE1 gene produced no major phenotype in erythrocyte cultures. (C) 2008 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.