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Phosphodiesterase type 5 enzyme

Phosphodiesterase type 5 enzyme

Phosphodiesterase type 5 enzyme

Cyclic nucleotide phosphodiesterases are important group of enzymes controlling the concentration of cGMP and cAMP which are the intracellular secondary messengers controlling various physiological processes. The phosphodiesterase superfamily is divided into 11 different families namely (PPDE1-PDE11), PDE5 being one of the family members.

Phosphodiesterase type 5 is a phosphoric-diester hydrolase enzyme that catalyzes the breakdown of phosphodiester bond by hydrolysis of cyclic nucleotide, particularly cyclic guanosine monophosphate (cGMP) to its corresponding 5′ nucleotide monophosphates (GMP). Phosphodiesterase type 5 has one subtype (PDE5A) which has four isoforms (PDE5A1-4) in human.


Structure of Phosphodiesterase type 5 enzyme

Phosphodiesterase type 5 consists of three domains: A C-terminal helical domain, N-terminal cyclin and a linker domain which is helical. The active site domain, in which the drug binds to the protein, is present at the joint portion of the three domains.


Distribution of Phosphodiesterase type 5 in human body

In humans, phosphodiesterase type 5 is mostly distributed in smooth muscle (visceral, vascular) and skeletal muscles. It can be found in kidneys, prostate, heart, liver, penis, urethra, bladder, uterus, corpus cavernosum, pancreas, clitoris and smooth muscles present in the wall of vagina. It is also found in cerebral Purkinje cells and gastric epithelial cells.


Role of Phosphodiesterase type 5 in human diseases

Nowadays, phosphodiesterase type 5 enzyme inhibitor is in limelight. The enzyme is a novel target for the treatment of erectile dysfunction and pulmonary hypertension. In human, L-arginine-nitric oxide-guanylyl cyclase-cyclic guanosine monophosphate pathway is involved in penile erection. A cascade of enzymatic reaction takes place in the process, starting from the release of nitric oxide in the cells to the synthesis of cAMP.

During sexual arousal, nitric oxide, which is produced from oxygen and L-arginine in presence of nitric oxide synthase, is released from nerves and endothelial cells which find its way into the cytoplasm of smooth muscle cells of penis. Nitric oxide then binds with guanylyl cyclase present in cytosol, triggering the formation of cGMP in presence of ATP. cGMP activates cGMP binding protein, protein kinase G and cGMP ion channels.

Activated protein kinase G then phosphorylates several proteins, and due to these protein interactions, there is a reduction of intracellular calcium levels. Reduced calcium levels results in relaxation of smooth muscles, venous constriction, arterial dilatation and increased blood flow into the penis and hence erection. Phosphodiesterase type 5 enzyme in turn inhibits penis erection by hydrolyzing cGMP to GMP in presence of zinc at the catalytic site. Thus PDE5 decreases cGMP level in smooth muscles.

Malfunction of PDE5 results in decreased cGMP level due to which relaxation of smooth muscle in the penile tissue does not occur. This causes erectile dysfunction. Sexual dysfunction is also caused by stress, diabetes, blood pressure, spinal cord injury, neurological disorders, cardiovascular diseases and prostatectomy surgery.

Substances like sildenafil citrate, vardenafil, tadalafil and udenafil are used in the treatment of erectile dysfunction. These drugs specifically bind to the catalytic site of PDE5 thereby inhibiting the activity of the enzyme.

This results in increased level of PDE5 in penis which leads to improved erections. Tadalafil is used in the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia. Sildenafil citrate and tadalafil are approved drugs by FDA for the treatment of pulmonary hypertension (PAH).

PDE5 inhibitors for the treatment of chronic obstructive pulmonary disease, cardiovascular diseases, premature ejaculation, female arousal disorder and other vascular diseases are in experimental stage.

Side effects of PDE5 inhibitor include nasal congestion, skin flushing, headache and gastrointestinal disorder.

Phosphodiesterase type 5 thus proves to be a novel enzyme target molecule for the discovery of more efficacious drugs for the treatment of sexual and pulmonary diseases.


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