What is a Phosphodiesterase?

A phosphodiesterase is a type of enzyme that catalyzes the cleavage of the phosphate linkage of nucleotide strands such as DNA or RNA. Many enzymes can carry out this reaction. The term, however, is usually applied to phosphodiesterases that cleave cyclic nucleotides that are important for transmitting signals within the cell. These enzymes are known as cyclic nucleotide phosphodiesterases (PDEs). Phosphodiesterase inhibitors can be used as drugs, and are used commercially to treat male erectile dysfunction and other conditions.

A nucleotide is a compound that has an aromatic base containing nitrogen, a sugar that is either ribose or deoxyribose, and a phosphate group. DNA and RNA are long strands of nucleotides with each nucleotide linked sequentially to the next and are polymers. A phosphate bond linkage is an important part of the polymerization of these nucleotide chains. Cyclic nucleotides have two phosphate groups linked to a ribose group in two different places. This makes the compound cyclic, enabling it to bind proteins differently.

The two cyclic nucleotides in all cells are cyclic AMP (cAMP) and cyclic GMP (cGMP). They have a single base of adenine and guanine, respectively. These compounds react in many different cellular processes, and are known as secondary messengers. The first signal is relayed from outside of the cell by the binding of a hormone or neurotransmitter. This binding then triggers an increase in cAMP or cGMP concentrations, which greatly amplifies the magnitude of the original signal.

Cyclic nucleotide phosphodiesterases degrade the cyclic nucleotide by cleaving a phosphate bond that keeps the nucleotide cyclic. This is known as phosphodiester bond cleavage, and causes degradation of the cyclic nucleotide. This degradation regulates the duration, localization, and amplitude of the signaling of the compound.

There are many types of this class of phosphodiesterase, specialized for different functions. As of 2010, mammals are known to have 11 families of cyclic nucleotide phosphodiesterase genes. Genes provide the blueprint for protein production, and it is estimated that there are more than 50 different cyclic phosphodiesterase proteins in mammalian cells.

The PDEs differ in many aspects, including their biochemical properties and which cyclic nucleotide they can act upon. These are part of the criteria used to assign them to families. Some degrade only cAMP, while others only affect cGMP. Other PDEs can degrade both of these cyclic nucleotides.

The diversity of reactions affected by these enzymes makes them promising targets for drug therapy. Inhibition of the PDEs prolongs the reaction being mediated by the cyclic nucleotide. The most prominent type of cyclic nucleotide phosphodiesterase inhibitor is that affecting Family Five, which inhibits cGMP degradation. These drugs are sildenafil, better known as Viagra®; tadalafil, also known as Cialis®; and vardenafil, more commonly known as Levitra®. This group of phosphodiesterase inhibitors is used to treat male erectile dysfunction — and more recently, other conditions such as high blood pressure.

In contrast, inhibitors of Family Three are used to treat acute heart failure. This type of enzyme increases the activity of cAMP and is inhibited by cGMP. These drugs are milrinone, brand name Primacor™, and inamrinone, also known as Inocor®. Cilostazol, like Pletal®, is another drug in this class, and is used to treat peripheral arterial disease.

The functions of many of the newly discovered cyclic nucleotide phosphodiesterase families are unknown. Recent work has identified inflammation as an area of regulation that may involve some of these enzymes. This suggests that there will be many more targets for disease intervention when the biochemistry and function of these enzymes becomes better understood.