Cyclic nucleotide specific phosphodiesterases of the kinetoplastida: A unified nomenclature

Kunz, Stefan; Beavo, Joseph A.; D’Angelo, Maximiliano A.; Flawiá, Mirtha M.; Francis, Sharron H.; Johner, Andrea; Laxman, Sunil; Oberholzer, Michael; Rascón, Ana; Shakur, Yasmin; Wentzinger, Laurent; Zoraghi, Roya; Seebeck, Thomas

doi:10.1016/j.molbiopara.2005.09.018

Cited by 38 publications

(32 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The genomes of kinetoplastids, including T. cruzi, encode four PDE families, termed TcrPDEA, B, C, and D (16) (Fig. 1), in contrast to the human genome, which contains 21 PDE genes categorized into 11 families.…”

Section: Trypanosoma Cruzi Phosphodiesterase C (Tcrpdec) Is a Potentimentioning

confidence: 99%

Biological and Structural Characterization of Trypanosoma cruzi Phosphodiesterase C and Implications for Design of Parasite Selective Inhibitors

Wang

Kunz

Chen

et al. 2012

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Cyclic nucleotide specific phosphodiesterases (PDEs) are essential enzymes in many parasitic protozoa and represent important new drug targets. Results: The crystallographic structure and enzymatic properties of Trypanosoma cruzi phosphodiesterase C (TcrPDEC) have been determined. Conclusion: A parasite-specific pocket next to the TcrPDEC active site might allow designing parasite-specific inhibitors. Significance: The findings highlight the potential of PDEs as anti-parasite drug targets.

show abstract

Section: Trypanosoma Cruzi Phosphodiesterase C (Tcrpdec) Is a Potentimentioning

confidence: 99%

Biological and Structural Characterization of Trypanosoma cruzi Phosphodiesterase C and Implications for Design of Parasite Selective Inhibitors

Wang

Kunz

Chen

et al. 2012

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…The genomes of the kinetoplastida code for four different class 1 PDEs and no other PDE classes, similar to the situation in the human genome. All kinetoplastid genomes for which sequence data are currently available contain the same complement of PDE genes [61] (Figure 1), and the respective PDE polypeptides are highly conserved between the species [62]. PDEA codes for a high-K m , cAMP-specific PDE [63].…”

Section: The Pdes Of T Brucei and L Majormentioning

confidence: 99%

Phosphodiesterase Inhibitors as a New Generation of Antiprotozoan Drugs: Exploiting the Benefit of Enzymes that are Highly Conserved Between Host and Parasite

Seebeck

Sterk²,

2011

Future Med. Chem.

Self Cite

View full text Add to dashboard Cite

Protozoan infections remain a major unsolved medical problem in many parts of our world. A major obstacle to their treatment is the blatant lack of medication that is affordable, effective, safe and easy to administer. For some of these diseases, including human sleeping sickness, very few compounds are available, many of them old and all of them fraught with toxic side effects. We explore a new concept for developing new-generation antiprotozoan drugs that are based on phosphodiesterase (PDE) inhibitors. Such inhibitors are already used extensively in human pharmacology. Given the high degree of structural similarity between the human and the protozoan PDEs, the vast expertise available in the human field can now be applied to developing disease-specific PDE inhibitors as new antiprotozoan drugs.

show abstract

“…It belongs to the large order of the kinetoplastida, which includes many medically and economically important pathogens of humans, their livestock, and their crops worldwide (27 (25,53). In T. brucei, the genes for T. brucei PDEB1 (TbrPDEB1; subsequently termed PDEB1) and TbrPDEB2 (PDEB2) are tandemly arranged on chromosome 9 and code for two very similar cAMP-specific PDEs, each with two GAF (mammalian cyclic GMP-dependent PDEs, Anabaena adenylyl cyclases, Escherichia coli FhlA) domains (21) in their N-terminal regions (38,57).…”

mentioning

confidence: 99%

The N Terminus of Phosphodiesterase TbrPDEB1 of Trypanosoma brucei Contains the Signal for Integration into the Flagellar Skeleton

et al. 2010

Self Cite

View full text Add to dashboard Cite

The precise subcellular localization of the components of the cyclic AMP (cAMP) signaling pathways is a crucial aspect of eukaryotic intracellular signaling. In the human pathogen Trypanosoma brucei, the strict control of cAMP levels by cAMP-specific phosphodiesterases is essential for parasite survival, both in cell culture and in the infected host. Among the five cyclic nucleotide phosphodiesterases identified in this organism, two closely related isoenzymes, T. brucei PDEB1 (TbrPDEB1) (PDEB1) and TbrPDEB2 (PDEB2) are predominantly responsible for the maintenance of cAMP levels. Despite their close sequence similarity, they are distinctly localized in the cell. PDEB1 is mostly located in the flagellum, where it forms an integral part of the flagellar skeleton. PDEB2 is mainly located in the cell body, and only a minor part of the protein localizes to the flagellum. The current study, using transfection of procyclic trypanosomes with green fluorescent protein (GFP) reporters, demonstrates that the N termini of the two enzymes are essential for determining their final subcellular localization. The first 70 amino acids of PDEB1 are sufficient to specifically direct a GFP reporter to the flagellum and to lead to its detergent-resistant integration into the flagellar skeleton. In contrast, the analogous region of PDEB2 causes the GFP reporter to reside predominantly in the cell body. Mutagenesis of selected residues in the N-terminal region of PDEB2 demonstrated that single amino acid changes are sufficient to redirect the reporter from a cell body location to stable integration into the flagellar skeleton.

show abstract

Cyclic nucleotide specific phosphodiesterases of the kinetoplastida: A unified nomenclature

Cited by 38 publications

References 22 publications

Biological and Structural Characterization of Trypanosoma cruzi Phosphodiesterase C and Implications for Design of Parasite Selective Inhibitors

Biological and Structural Characterization of Trypanosoma cruzi Phosphodiesterase C and Implications for Design of Parasite Selective Inhibitors

Phosphodiesterase Inhibitors as a New Generation of Antiprotozoan Drugs: Exploiting the Benefit of Enzymes that are Highly Conserved Between Host and Parasite

The N Terminus of Phosphodiesterase TbrPDEB1 of Trypanosoma brucei Contains the Signal for Integration into the Flagellar Skeleton

Contact Info

Product

Resources

About