Summary: 3'5'-cyclic nucleotide phosphodiesterase
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Cyclic nucleotide phosphodiesterase Edit Wikipedia article
|3',5'-cyclic nucleotide phosphodiesterase|
Phosphodiesterase 4D hexamer, Human
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
3'5'-cyclic nucleotide phosphodiesterases (EC 188.8.131.52, cyclic 3',5'-mononucleotide phosphodiesterase, PDE, cyclic 3',5'-nucleotide phosphodiesterase, cyclic 3',5'-phosphodiesterase, 3',5'-nucleotide phosphodiesterase, 3':5'-cyclic nucleotide 5'-nucleotidohydrolase, 3',5'-cyclonucleotide phosphodiesterase, 3', 5'-cyclic nucleoside monophosphate phosphodiesterase, 3': 5'-monophosphate phosphodiesterase (cyclic CMP), cytidine 3':5'-monophosphate phosphodiesterase (cyclic CMP), cyclic 3',5-nucleotide monophosphate phosphodiesterase, nucleoside 3',5'-cyclic phosphate diesterase, nucleoside-3',5-monophosphate phosphodiesterase) are a family of phosphodiesterases. Generally, these enzymes hydrolyze some nucleoside 3’,5’-cyclic phosphate to some nucleoside 5’-phosphate thus controlling the cellular levels of the cyclic second messengers and the rates of their degradation. Some examples of nucleoside 3’,5’-cyclic phosphate include:
- 3',5'-cyclic AMP
- 3',5'-cyclic dAMP
- 3',5'-cyclic IMP
- 3',5'-cyclic GMP
- 3',5'-cyclic CMP
As per Andrew T. Bender and Joseph A. Beavo, there are 11 distinct phosphodiesterase families (PDE1-PDE11) with a variety in isoforms and splicing having unique three-dimensional structure, kinetic properties, modes of regulation, intracellular localization, cellular expression, and inhibitor sensitivities.
Retinal 3',5'-cGMP phosphodiesterase (PDE) is located in photoreceptor outer segments and is an important enzyme in phototransduction.
PDE in rod cells are oligomeric, made up of two heavy catalytic subunits, α (90 kDa) and β (85 kDa,) and two lighter inhibitory γ subunits (11 kDa each).
PDE in rod cells are activated by transducin. Transducin is a G protein which upon GDP/GTP exchange in the transducin α subunit catalyzed by photolyzed rhodopsin. The transducin α subunit (Tα) is released from the β and γ complex and diffuses into the cytoplasmic solution to interact and activate PDE.
Activation by Tα
There are two proposed mechanisms for the activation of PDE. The first proposes that the two inhibitory subunits are differentially bound, sequentially removable and exchangeable between the native complex PDEαβγ2 and PDEαβ. GTP-bound-Tα removes the inihibitory γ subunits one at a time from the αβ catalytic subunits. The second and more likely mechanism states that the GTP-Tα complex binds to the γ subunits but rather than dissociating from the catalytic subunits, it stays with the PDEαβ complex. Binding of the GTP-Tα complex to the PDE γ subunits likely causes a conformational shift in the PDE, allowing better access to the site of cGMP hydrolysis on PDEαβ.
The binding site for PDE α and β subunits are likely to be in the central region of the PDE γ subunits. The C-terminal of the PDE γ subunit is likely to be involved in inhibition of PDE α and β subunits, the binding site for Tα and GTPase accelerating activity for the GTP-bound Tα.
In cones, PDE is a homodimer of alpha chains, associated with several smaller subunits. Both rod and cone PDEs catalyze the hydrolysis of cAMP or cGMP to their 5’ monophosphate form. Both enzymes also bind cGMP with high affinity. The cGMP-binding sites are located in the N-terminal half of the protein sequence, while the catalytic core resides in the C-terminal portion.
Human genes encoding proteins containing this domain include:
- PDE1A, PDE1B, PDE1B2, PDE1C, PDE2A, PDE3A, PDE3B, PDE4A, PDE4B, PDE4B5, PDE4C, PDE4D,
- PDE5A, PDE6A, PDE6B, PDE6C, PDE7A, PDE7B, PDE8A, PDE8B, PDE9A,
- PDE10A, PDE10A2, PDE11A,
- Bender, Andrew T.; Beavo, Joseph A. (September 2006). "Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use". Pharmacological Reviews. 58 (3): 488–520. doi:10.1124/pr.58.3.5.
- Arkinstall S, Watson SP (1994). "Opsins". The G-protein linked receptor factsbook. Boston: Academic Press. pp. 214–222. ISBN 0-12-738440-5.
- Deterre P, Bigay J, Forquet F, Robert M, Chabre M (April 1988). "cGMP phosphodiesterase of retinal rods is regulated by two inhibitory subunits". Proc. Natl. Acad. Sci. U.S.A. 85 (8): 2424–8. doi:10.1073/pnas.85.8.2424. PMC . PMID 2833739.
- Kroll S, Phillips WJ, Cerione RA (March 1989). "The regulation of the cyclic GMP phosphodiesterase by the GDP-bound form of the alpha subunit of transducin". J. Biol. Chem. 264 (8): 4490–7. PMID 2538446.
- Liu Y, Arshavsky VY, Ruoho AE (January 1999). "Interaction sites of the C-terminal region of the cGMP phosphodiesterase inhibitory subunit with the GDP-bound transducin alpha-subunit". Biochem. J. 337 (2): 281–8. doi:10.1042/0264-6021:3370281. PMC . PMID 9882626.
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3'5'-cyclic nucleotide phosphodiesterase Provide feedback
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This tab holds annotation information from the InterPro database.
InterPro entry IPR002073
The cyclic nucleotide phosphodiesterases (PDE) comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They are divided into 11 families. They regulate the localisation, duration and amplitude of cyclic nucleotide signalling within subcellular domains. PDEs are therefore important for signal transduction.
PDE enzymes are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties. Inhibitors include: Roflumilast for chronic obstructive pulmonary disease and asthma [PUBMED:18447606], Sildenafil for erectile dysfunction [PUBMED:18367027] and Cilostazol for peripheral arterial occlusive disease [PUBMED:18436153], amongst others.
Retinal 3',5'-cGMP phosphodiesterase is located in photoreceptor outer segments: it is light activated, playing a pivotal role in signal transduction. In rod cells, PDE is oligomeric, comprising an alpha-, a beta- and 2 gamma-subunits, while in cones, PDE is a homodimer of alpha chains, which are associated with several smaller subunits. Both rod and cone PDEs catalyse the hydrolysis of cAMP or cGMP to the corresponding nucleoside 5' monophosphates, both enzymes also binding cGMP with high affinity. The cGMP-binding sites are located in the N-terminal half of the protein sequence, while the catalytic core resides in the C-terminal portion.This entry represents the catalytic domain of PDE which is multihelical and can be divided into three subdomains.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||3',5'-cyclic-nucleotide phosphodiesterase activity (GO:0004114)|
|Biological process||signal transduction (GO:0007165)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Number in seed:||322|
|Number in full:||5152|
|Average length of the domain:||216.70 aa|
|Average identity of full alignment:||31 %|
|Average coverage of the sequence by the domain:||33.00 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||18|
|Download:||download the raw HMM for this family|
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How the sunburst is generated
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
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We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There are 3 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the PDEase_I domain has been found. There are 564 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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