Phosphodiesterase 9: Insights from protein structure and role in therapeutics

Singh, Namrata; Patra, Sanjukta

doi:10.1016/j.lfs.2014.04.007

Cited by 22 publications

(22 citation statements)

References 86 publications

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“…Ca-alpha1T is also involved in neural pathways and behavior [82]. Pde9 has no reported function in Drosophila , but its human homolog (63% sequence similarity) is involved in cGMP signaling, hyperglycemia, diabetes, learning, differentiation of stem cells, and neurodegenerative disease [83]. …”

Section: Resultsmentioning

confidence: 99%

The genetic basis for variation in resistance to infection in the Drosophila melanogaster genetic reference panel

Wang

Leger

2017

PLoS Pathog

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Individuals vary extensively in the way they respond to disease but the genetic basis of this variation is not fully understood. We found substantial individual variation in resistance and tolerance to the fungal pathogen Metarhizium anisopliae Ma549 using the Drosophila melanogaster Genetic Reference Panel (DGRP). In addition, we found that host defense to Ma549 was correlated with defense to the bacterium Pseudomonas aeruginosa Pa14, and several previously published DGRP phenotypes including oxidative stress sensitivity, starvation stress resistance, hemolymph glucose levels, and sleep indices. We identified polymorphisms associated with differences between lines in both their mean survival times and microenvironmental plasticity, suggesting that lines differ in their ability to adapt to variable pathogen exposures. The majority of polymorphisms increasing resistance to Ma549 were sex biased, located in non-coding regions, had moderately large effect and were rare, suggesting that there is a general cost to defense. Nevertheless, host defense was not negatively correlated with overall longevity and fecundity. In contrast to Ma549, minor alleles were concentrated in the most Pa14-susceptible as well as the most Pa14-resistant lines. A pathway based analysis revealed a network of Pa14 and Ma549-resistance genes that are functionally connected through processes that encompass phagocytosis and engulfment, cell mobility, intermediary metabolism, protein phosphorylation, axon guidance, response to DNA damage, and drug metabolism. Functional testing with insertional mutagenesis lines indicates that 12/13 candidate genes tested influence susceptibility to Ma549. Many candidate genes have homologs identified in studies of human disease, suggesting that genes affecting variation in susceptibility are conserved across species.

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Section: Resultsmentioning

confidence: 99%

The genetic basis for variation in resistance to infection in the Drosophila melanogaster genetic reference panel

Wang

Leger

2017

PLoS Pathog

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“…The gross structure was further established by analyses of its 2D NMR spectra. The relative configuration of 2 was assigned to be the same as that of 1 based on the interpretation of the NOE correlations (H-9″/H-9β and H-7/H-9β) and 1 Compound 3, obtained as a light yellow oil, had the molecular formula C 32 H 36 O 7 , as established by 13 C NMR data and HRESIMS. The NMR data of 3 showed similarity to those of 2 with major differences being attributable to the presence of an additional methoxy group in the A-ring of 3.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…1 Phosphodiesterases (PDEs) catalyze the hydrolysis of intracellular cAMP and cGMP and thus play key roles in the cellular process. Among the 11-membered PDE isoforms, PDE9 has the lowest K m among cGMP-specific PDE families.…”

mentioning

confidence: 99%

(±)-Torreyunlignans A–D, Rare 8–9′ Linked Neolignan Enantiomers as Phosphodiesterase-9A Inhibitors from Torreya yunnanensis

et al. 2014

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(±)-Torreyunlignans A-D (1a/1b-4a/4b), four pairs of new 8-9' linked neolignan enantiomers featuring a rare (E)-2-styryl-1,3-dioxane moiety, were isolated from the trunk of Torreya yunnanensis. The structures were determined by combined spectroscopic and chemical methods, and the absolute configurations were elucidated by ECD calculations. The compounds were screened by using tritium-labeled adenosine 3',5'-cyclic monophosphate ([(3)H]-cGMP) as a substrate for inhibitory affinities against phosphodiesterase-9A (PDE9A), which is a potential target for the treatment of diabetes and Alzheimer's disease. All of the enantiomers exhibited inhibition against PDE9A with IC50 values ranging from 5.6 to 15.0 μM. This is the first report of PDE9A inhibitors from nature.

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“…The remaining PDE families are capable of degrading both substrates. PDE9 inhibitors have been studied for their potential applications to treat diabetes (Deninno et al, 2009;Shao et al, 2014) and central nervous system diseases such as Alzheimer's disease (Wunder et al, 2005;van der Staay et al, 2008;Verhoest et al, 2009Verhoest et al, , 2012Hutson et al, 2011;Vardigan et al, 2011;Claffey et al, 2012;Kleiman et al, 2012;Kroker et al, 2012Kroker et al, , 2014Liddie et al, 2012;Schwam et al, 2014;Singh and Patra, 2014;Heckman et al, 2015;Nagy et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor

et al. 2015

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Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S), has an IC 50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors.

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Phosphodiesterase 9: Insights from protein structure and role in therapeutics

Cited by 22 publications

References 86 publications

The genetic basis for variation in resistance to infection in the Drosophila melanogaster genetic reference panel

The genetic basis for variation in resistance to infection in the Drosophila melanogaster genetic reference panel

(±)-Torreyunlignans A–D, Rare 8–9′ Linked Neolignan Enantiomers as Phosphodiesterase-9A Inhibitors from Torreya yunnanensis

Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor

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