A phosphodiesterase is any enzyme

Enzyme

Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 that breaks a phosphodiester bond

Phosphodiester bond

A phosphodiester bond is a group of strong covalent bonds between a phosphate group and two 5-carbon ring carbohydrates over two ester bonds. Phosphodiester bonds are central to all known life, as they make up the backbone of each helical strand of DNA...

. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide

Cyclic nucleotide

A cyclic nucleotide is any nucleotide in which the phosphate group is bonded to two of the sugar's hydroxyl groups, forming a cyclical or ring structure.These include:* cyclic AMP* cyclic GMP* cyclic ADP-ribose...

 phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipase

Phospholipase

A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze:*Phospholipase A...

s C

Phospholipase C

Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...

 and D

Phospholipase D

Phospholipase D is an enzyme which is located in the plasma membrane and catalyzes the hydrolysis of phosphatidylcholine to form phosphatidic acid , releasing the soluble choline headgroup into the cytosol...

, autotaxin

Autotaxin

Autotaxin also known as ectonucleotide pyrophosphatase/phosphodiesterase family member 2 is an enzyme that in humans is encoded by the ENPP2 gene.- Function :...

, sphingomyelin phosphodiesterase

Sphingomyelin phosphodiesterase

Sphingomyelin phosphodiesterase or simply Sphingomyelinase is a hydrolase enzyme that is involved in sphingolipid metabolism reactions. SMase is a member of the DNase I superfamily of enzymes and is responsible for breaking sphingomyelin down into phosphocholine and ceramide...

, DNases, RNases, and restriction endonucleases (which all break the phosphodiester backbone of DNA

DNA

Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

 or RNA

RNA

Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....

), as well as numerous less-well-characterized small-molecule phosphodiesterases.

The cyclic nucleotide phosphodiesterase

Cyclic nucleotide phosphodiesterase

3'5'-cyclic nucleotide phosphodiesterase is a family of phosphodiesterases. These enyzmes catalyze the following reaction:* nucleoside 3',5'-cyclic phosphate + H2O = nucleoside 5'-phosphate...

s comprise a group of enzymes that degrade the phosphodiester bond

Phosphodiester bond

A phosphodiester bond is a group of strong covalent bonds between a phosphate group and two 5-carbon ring carbohydrates over two ester bonds. Phosphodiester bonds are central to all known life, as they make up the backbone of each helical strand of DNA...

 in the second messenger molecules cAMP

Cyclic adenosine monophosphate

Cyclic adenosine monophosphate is a second messenger important in many biological processes...

 and cGMP

Cyclic guanosine monophosphate

Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...

. They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. PDEs are therefore important regulators of signal transduction

Signal transduction

Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...

 mediated by these second messenger molecules.

History

These multiple forms (isoforms or subtypes) of phosphodiesterase were isolated from rat brain using polyacrylamide gel electrophoresis in the early 1970s and were soon afterward shown to be selectively inhibited by a variety of drugs in brain and other tissues.

The potential for selective phosphodiesterase inhibitor

Phosphodiesterase inhibitor

A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase , therefore preventing the inactivation of the intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate by the respective PDE...

s to be used as therapeutic agents was predicted as early as 1977 by Weiss and Hait. This prediction has now come to pass in a variety of fields (e.g. Viagra as a PDE5 inhibitor and Diazepam

Diazepam

Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...

 as a PDE4 inhibitor

PDE4 inhibitor

A phosphodiesterase type 4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 on cyclic adenosine monophosphate . It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in...

 ).

Classification and nomenclature

The PDE superfamily of enzymes is classified into 11 families, namely PDE1

PDE1

PDE1 is a phosphodiesterase enzyme also known as calcium- and calmodulin-dependent phosphodiesterase. It is one of the 11 families of phosphodiesterase . PDE1 has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms...

-PDE11, in mammals. The classification is based on:

• amino acid
  Amino acid
  Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
  
   sequences
• substrate specificities
• regulatory properties
• pharmacological properties
• tissue distribution

Different PDEs of the same family are functionally related despite the fact that their amino acid sequences can show considerable divergence. PDEs have different substrate specificities. Some are cAMP-selective hydrolases (PDE4, 7 and 8); others are cGMP-selective (PDE5, 6, and 9). Others can hydrolyse both cAMP and cGMP (PDE1, 2, 3, 10, and 11). PDE3

PDE3

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....

 is sometimes referred to as cGMP-inhibited phosphodiesterase. Although PDE2

PDE2

The PDE2 enzyme is one of 21 different phosphodiesterases 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...

 can hydrolyze both cyclic nucleotides, binding of cGMP to the regulatory GAF-B domain will increase cAMP affinity and hydrolysis to the detriment of cGMP. This mechanism, as well as others, allows for cross-regulation of the cAMP and cGMP pathways.

The nomenclature for PDE indicates PDE family by an Arabic numeral that is followed by a capital letter to denote the gene within a family. A second Arabic numeral indicates the splice variant derived from a single gene (e.g., PDE1C3: family 1, gene C, splicing variant 3)

Clinical significance

Phosphodiesterase enzymes are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties.

Inhibitors of PDE

Phosphodiesterase inhibitor

A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase , therefore preventing the inactivation of the intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate by the respective PDE...

 can prolong or enhance the effects of physiological processes mediated by cAMP

Cyclic adenosine monophosphate

Cyclic adenosine monophosphate is a second messenger important in many biological processes...

 or cGMP

Cyclic guanosine monophosphate

Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...

 by inhibition of their degradation by PDE.

Sildenafil

Sildenafil

Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer...

 (Viagra) is an inhibitor of cGMP-specific phosphodiesterase type 5, which enhances the vasodilatory effects of cGMP in the corpus cavernosum

Corpus cavernosum

Corpus cavernosum may refer to:* corpus cavernosum clitoridis* corpus cavernosum penis* "corpus cavernosum urethrae" was used for corpus spongiosum in older texts* corpus cavernosum conchae...

 and is used to treat erectile dysfunction

Erectile dysfunction

Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....

. Sildenafil is also currently being investigated for its myo- and cardioprotective effects, with particular interest being given to the compound's therapeutic value in the treatment of Duchenne muscular dystrophy

Duchenne muscular dystrophy

Duchenne muscular dystrophy is a recessive X-linked form of muscular dystrophy, which results in muscle degeneration, difficulty walking, breathing, and death. The incidence is 1 in 3,000 boys. Females and males are affected, though females are rarely affected and are more often carriers...

  and benign prostatic hyperplasia

Benign prostatic hyperplasia

Benign prostatic hyperplasia also known as benign prostatic hypertrophy , benign enlargement of the prostate , and adenofibromyomatous hyperplasia, refers to the increase in size of the prostate....

 .

PDE inhibitors have been identified as new potential therapeutics in areas such as pulmonary arterial hypertension

Hypertension

Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

, coronary heart disease

Coronary heart disease

Coronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients. It is sometimes also called coronary heart disease...

, dementia

Dementia

Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...

, depression

Depression (mood)

Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...

, and schizophrenia

Schizophrenia

Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...

.

Cilostazol (Pletal) inhibits PDE3

PDE3

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....

. This inhibition allows red blood cells to be more able to bend. This is useful in conditions such as intermittent claudication

Intermittent claudication

Intermittent claudication is a clinical diagnosis given for muscle pain , classically in the calf muscle, which occurs during exercise, such as walking, and is relieved by a short period of rest.Claudication derives from the Latin verb claudicare, "to limp".-Signs:One of the hallmarks of arterial...

, as the cells can maneuver through constricted veins and arteries more easily.

Xanthins, caffeine, theobromine, and thyroid hormone are phosphodiesterase inhibitors (enhance lipolysis as inhibition of phosphodiesterase enzyme, thereby preserving cAMP, also activating kinase enzyme, which phosphorylates hormone-sensitive lipase and activates lipolysis).