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Function

Human PDE5 is the 5th isoform of the 12 known phosphodiesterases. This enzymes family is responsible for the hydrolysis of cGMP and cAMP into GMP and AMP. PDE5 specifically catalyses cGMP hydrolysis into 5'GMP. The cGMP is an usual second messager in cell signalling pathways, like NO synthesis. By degradating nucleotides, this enzyme of class I regulates the cGMP concentration in the organism by an allosteric regulation system.

PDE5 function affects the smooth muscle, blood vessels or penis, uterus and intestines.

Structural highlights

PDE5 is a homodimeric protein of 875 amino acids long. This protein is composed of several important domains:

• • pol-GLY (10-24 amino acids) in Ntermini (structural importance).
  • GAFA (164-314 amino acids)
  • GAFB (346-503 amino acids)
  • Catalytic domain (588-853 amino acids) in Ctermini involved in cGMP hydrolysis.

The full structure of PDE5 has not been crystallized contrary to this of isolated domains of the protein. GAFA and GAFB are homologous domains and allosteric binding site of cGMP.

Catalytic activity

PDE5 is a phosphodiesterase. cGMP could bind the catalytic domain thanks to hydrogen bonds made with Gln775 and Gln817 and coordination bonds made with Zn2+ and Mg2+ in the catalytic site. To see these interactions, report to Sildenafil in Inhibitors and medical application. cGMP is hydrolyzed in GMP. The catalytic chemical reaction deals with breaking a phosphodiester bound in cGMP between the 3'O of the guanoside and the phosphate of cGMP: cGMP + H20 => GMP.

Some residues could be affected by post traductional modifications :

phosphorylation : S60, S86, S92, S102, S104, S108, T111, T127, T137, S869. acylation : K364. ubiquitinylation : K714. The ubiquitinylation of (in fushia) and the phosphorylation of are involved in the binding of cGMP to PDE5 catalytic domain.

Inhibitors and medical application

Inhibitors of PDE5 prevent cGMP from binding the catalytic site by competititve inhibition. They have more affinity for this domain than cGMP. Sildenafil (active substance of Viagra) binds to PDE5 catalytic domain through: hydrogen bonds made between Gln775 and Gln817 of PDE5 (green) and (red) coordination bond made with coordination made with

Allosteric activation

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