Abstract
Trypanosoma cruzi phosphodiesterase C (TcrPDEC) is a potential new drug target for the treatment of Chagas disease but has not been well studied. This study reports the enzymatic properties of various kinetoplastid PDECs and the crystal structures of the unliganded TcrPDEC1 catalytic domain and its complex with an inhibitor. Mutations of PDEC during the course of evolution led to inactivation of PDEC in Trypanosoma brucei/Trypanosoma evansi/Trypanosoma congolense, whereas the enzyme is active in all other kinetoplastids. The TcrPDEC1 catalytic domain hydrolyzes both cAMP and cGMP with a K(m) of 23.8 μm and a k(cat) of 31 s(-1) for cAMP and a K(m) of 99.1 μm and a k(cat) of 17 s(-1) for cGMP, thus confirming its dual specificity. The crystal structures show that the N-terminal fragment wraps around the TcrPDEC catalytic domain and may thus regulate its enzymatic activity via direct interactions with the active site residues. A PDE5 selective inhibitor that has an IC(50) of 230 nm for TcrPDEC1 binds to TcrPDEC1 in an orientation opposite to that of sildenafil. This observation, together with the screen of the inhibitory potency of human PDE inhibitors against TcrPDEC, implies that the scaffold of some human PDE inhibitors might be used as the starting model for design of parasite PDE inhibitors. The structural study also identified a unique parasite pocket that neighbors the active site and may thus be valuable for the design of parasite-specific inhibitors.
Highlights
Cyclic nucleotide specific phosphodiesterases (PDEs) are essential enzymes in many parasitic protozoa and represent important new drug targets
This study reports the enzymatic properties of various kinetoplastid PDECs and the crystal structures of the unliganded TcrPDEC1 catalytic domain and its complex with an inhibitor
We report the enzymatic properties of various kinetoplastid PDECs, and the crystal structures of the unliganded TcrPDEC1 and its complex with the inhibitor wyq16
Summary
Cyclic nucleotide specific phosphodiesterases (PDEs) are essential enzymes in many parasitic protozoa and represent important new drug targets. Trypanosoma cruzi phosphodiesterase C (TcrPDEC) is a potential new drug target for the treatment of Chagas disease but has not been well studied. This study reports the enzymatic properties of various kinetoplastid PDECs and the crystal structures of the unliganded TcrPDEC1 catalytic domain and its complex with an inhibitor. Disruption of cyclic nucleotide signaling has been shown to eliminate Trypanosoma brucei infection from the host [9] In this context, PDE inhibitors might constitute a new class of potent drug candidates for protozoal infections. These results provide guidelines for the design of TcrPDEC inhibitors for the treatment of Chagas disease. We report the enzymatic properties of various kinetoplastid PDECs, and the crystal structures of the unliganded TcrPDEC1 and its complex with the inhibitor wyq
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