PDE4A

Last updated
PDE4A
Protein PDE4A PDB 1loi.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PDE4A , DPDE2, PDE4, PDE46, phosphodiesterase 4A
External IDs OMIM: 600126; MGI: 99558; HomoloGene: 4520; GeneCards: PDE4A; OMA:PDE4A - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001111307
NM_001111308
NM_001111309
NM_001243121
NM_006202

Contents

NM_019798
NM_183408
NM_001310750

RefSeq (protein)

NP_001104777
NP_001104778
NP_001104779
NP_001230050
NP_006193

NP_001297679
NP_062772
NP_899668

Location (UCSC) Chr 19: 10.42 – 10.47 Mb Chr 9: 21.08 – 21.12 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

cAMP-specific 3',5'-cyclic phosphodiesterase 4A is an enzyme that in humans is encoded by the PDE4A gene. [5] [6]

Function

The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase (PDE) family, and PDE4 subfamily. This PDE hydrolyzes the secondary messenger, cAMP, which is a regulator and mediator of a number of cellular responses to extracellular signals. Thus, by regulating the cellular concentration of cAMP, this protein plays a key role in many important physiological processes. [6] Recently, it has been shown through the use of PDE4A knock out mice that PDE4A may play a role in the regulation of anxiety and emotional memory. [7]

Clinical significance

PDE4A inhibition is a target of a number of drugs including: [8] [9] [10]

Related Research Articles

<span class="mw-page-title-main">Phosphodiesterase inhibitor</span> Drug

A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.

<span class="mw-page-title-main">Cyclic nucleotide</span> Cyclic nucleic acid

A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, and a single phosphate group. As can be seen in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) images, the 'cyclic' portion consists of two bonds between the phosphate group and the 3' and 5' hydroxyl groups of the sugar, very often a ribose.

<span class="mw-page-title-main">Phosphodiesterase</span> Class of enzymes

A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, phosphodiesterase refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases.

cGMP-specific phosphodiesterase type 5 Mammalian protein found in Homo sapiens

Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum and the retina. It has also been recently discovered to play a vital role in the cardiovascular system.

<span class="mw-page-title-main">Cyclic nucleotide phosphodiesterase</span> Class of enzymes

3′,5′-cyclic-nucleotide phosphodiesterases (EC 3.1.4.17) are a family of phosphodiesterases. Generally, these enzymes hydrolyze a nucleoside 3′,5′-cyclic phosphate to a nucleoside 5′-phosphate:

<span class="mw-page-title-main">Rolipram</span> Chemical compound

Rolipram is a selective phosphodiesterase-4 inhibitor discovered and developed by Schering AG as a potential antidepressant drug in the early 1990s. It served as a prototype molecule for several companies' drug discovery and development efforts. Rolipram was discontinued after clinical trials showed that its therapeutic window was too narrow; it could not be dosed at high enough levels to be effective without causing significant gastrointestinal side effects.

<span class="mw-page-title-main">Phosphodiesterase 3</span> Class of enzymes

PDE3 is a phosphodiesterase. The PDEs belong to at least eleven related gene families, which are different in their primary structure, substrate affinity, responses to effectors, and regulation mechanism. Most of the PDE families are composed of more than one gene. PDE3 is clinically significant because of its role in regulating heart muscle, vascular smooth muscle and platelet aggregation. PDE3 inhibitors have been developed as pharmaceuticals, but their use is limited by arrhythmic effects and they can increase mortality in some applications.

Phosphodiesterase 1, PDE1, EC 3.1.4.1, systematic name oligonucleotide 5-nucleotidohydrolase) is a phosphodiesterase enzyme also known as calcium- and calmodulin-dependent phosphodiesterase. It is one of the 11 families of phosphodiesterase (PDE1-PDE11). Phosphodiesterase 1 has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms. The various isoforms exhibit different affinities for cAMP and cGMP.

<span class="mw-page-title-main">Phosphodiesterase 2</span> Class of enzymes

The PDE2 enzyme is one of 21 different phosphodiesterases (PDE) found in mammals. These different PDEs can be subdivided to 11 families. The different PDEs of the same family are functionally related despite the fact that their amino acid sequences show considerable divergence. The PDEs have different substrate specificities. Some are cAMP selective hydrolases, others are cGMP selective hydrolases and the rest can hydrolyse both cAMP and cGMP.

<span class="mw-page-title-main">PDE4D</span> Protein-coding gene in the species Homo sapiens

cAMP-specific 3',5'-cyclic phosphodiesterase 4D is an enzyme that in humans is encoded by the PDE4D gene.

<span class="mw-page-title-main">PRKAR2A</span> Protein-coding gene in the species Homo sapiens

cAMP-dependent protein kinase type II-alpha regulatory subunit is an enzyme that in humans is encoded by the PRKAR2A gene.

<span class="mw-page-title-main">PDE4B</span> Protein-coding gene in the species Homo sapiens

cAMP-specific 3',5'-cyclic phosphodiesterase 4B is an enzyme that in humans is encoded by the PDE4B gene.

<span class="mw-page-title-main">PDE11A</span> Protein-coding gene in the species Homo sapiens

Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A is an enzyme that in humans is encoded by the PDE11A gene.

<span class="mw-page-title-main">PDE7A</span> Protein-coding gene in the species Homo sapiens

High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A is an enzyme that in humans is encoded by the PDE7A gene. Mammals possess 21 cyclic nucleotide phosphodiesterase (PDE) genes that are pharmacologically grouped into 11 families. PDE7A is one of two genes in the PDE7 family, the other being PDE7B. The PDE7 family, along with the PDE4 and PDE8 families, are cAMP-specific, showing little to no activity against 3', 5'-cyclic guanosine monophosphate (cGMP).

<span class="mw-page-title-main">PDE4C</span> Protein-coding gene in the species Homo sapiens

cAMP-specific 3',5'-cyclic phosphodiesterase 4C is an enzyme that in humans is encoded by the PDE4C gene.

<span class="mw-page-title-main">PDE4 inhibitor</span> Class of chemical compounds

A phosphodiesterase-4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system.

<span class="mw-page-title-main">Piclamilast</span> Chemical compound

Piclamilast, is a selective PDE4 inhibitor. It is comparable to other PDE4 inhibitors for its anti-inflammatory effects. It has been investigated for its applications to the treatment of conditions such as chronic obstructive pulmonary disease, bronchopulmonary dysplasia and asthma. It is a second generation compound that exhibits structural functionalities of the PDE4 inhibitors cilomilast and roflumilast. The structure for piclamilast was first elucidated in a 1995 European patent application. The earliest mention of the name "piclamilast" was used in a 1997 publication.

<span class="mw-page-title-main">Filaminast</span> Chemical compound

Filaminast was a drug candidate developed by Wyeth-Ayerst. It is a phosphodiesterase 4 inhibitor and an analog of rolipram, which served as a prototype molecule for several development efforts. It was discontinued after a Phase II trial showed that its therapeutic window was too narrow; it could not be dosed high enough without causing significant side effects, which was a problem with the rolipram class of molecules.

3′,5′-cyclic-AMP phosphodiesterase (EC 3.1.4.53, cAMP-specific phosphodiesterase, cAMP-specific PDE, PDE1, PDE2A, PDE2B, PDE4, PDE7, PDE8, PDEB1, PDEB2) is an enzyme with systematic name 3′,5′-cyclic-AMP 5′-nucleotidohydrolase. It catalyses the following reaction

Phosphodiesterases (PDEs) are a superfamily of enzymes. This superfamily is further classified into 11 families, PDE1 - PDE11, on the basis of regulatory properties, amino acid sequences, substrate specificities, pharmacological properties and tissue distribution. Their function is to degrade intracellular second messengers such as cyclic adenine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which leads to several biological processes like effect on intracellular calcium level by the Ca2+ pathway.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000065989 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032177 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Milatovich A, Bolger G, Michaeli T, Francke U (Mar 1994). "Chromosome localizations of genes for five cAMP-specific phosphodiesterases in man and mouse". Somatic Cell and Molecular Genetics. 20 (2): 75–86. doi:10.1007/BF02290677. PMID   8009369. S2CID   19182571.
  6. 1 2 "PDE4A phosphodiesterase 4A, cAMP-specific ( Homo sapiens )". Entrez Gene. 2012-03-04. Retrieved 2012-04-02.
  7. Hansen RT, Conti M, Zhang H-T (2014). "Mice deficient in phosphodiesterase-4A display anxiogenic-like behavior". Psychopharmacology. 231 (15): 2941–2954. doi:10.1007/s00213-014-3480-y. PMID   24563185. S2CID   13542300.
  8. Rena G, Begg F, Ross A, MacKenzie C, McPhee I, Campbell L, Huston E, Sullivan M, Houslay MD (May 2001). "Molecular cloning, genomic positioning, promoter identification, and characterization of the novel cyclic amp-specific phosphodiesterase PDE4A10" (PDF). Molecular Pharmacology. 59 (5): 996–1011. doi:10.1124/mol.59.5.996. PMID   11306681.
  9. Wallace DA, Johnston LA, Huston E, MacMaster D, Houslay TM, Cheung YF, Campbell L, Millen JE, Smith RA, Gall I, Knowles RG, Sullivan M, Houslay MD (Jun 2005). "Identification and characterization of PDE4A11, a novel, widely expressed long isoform encoded by the human PDE4A cAMP phosphodiesterase gene". Molecular Pharmacology. 67 (6): 1920–34. doi:10.1124/mol.104.009423. PMID   15738310. S2CID   1758221.
  10. Mackenzie KF, Topping EC, Bugaj-Gaweda B, Deng C, Cheung YF, Olsen AE, Stockard CR, High Mitchell L, Baillie GS, Grizzle WE, De Vivo M, Houslay MD, Wang D, Bolger GB (Apr 2008). "Human PDE4A8, a novel brain-expressed PDE4 cAMP-specific phosphodiesterase that has undergone rapid evolutionary change". The Biochemical Journal. 411 (2): 361–9. doi:10.1042/BJ20071251. PMC   4337886 . PMID   18095939.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.