Cyclic nucleotide phosphodiesterase

3'5'-cyclic nucleotide phosphodiesterases are a family of phosphodiesterases. Generally, these enzymes hydrolyze some nucleoside 3’,5’-cyclic phosphate to some nucleoside 5’-phosphate. Some examples of nucleoside 3’,5’-cyclic phosphate include:

• 3',5'-cyclic AMP
• 3',5'-cyclic dAMP
• 3',5'-cyclic IMP
• 3',5'-cyclic GMP
• 3',5'-cyclic CMP

Function

Phototransduction

Retinal 3',5'-cGMP phosphodiesterase (EC 3.1.4.17) (PDE) is located in photoreceptor outer segments and is an important enzyme in phototransduction.^[1]

PDE in rod cells are oligomeric, made up of two heavy catalytic subunits, α (90 kDa) and β (85 kDa,) and two lighter inhibitory γ subunits (11 kDa each).^[2]

PDE in rod cells are activated by transducin. Transducin is a G protein which upon GDP/GTP exchange in the transducin α subunit catalyzed by photolyzed rhodopsin. The transducin α subunit (Tα) is released from the β and γ complex and diffuses into the cytoplasmic solution to interact and activate PDE.

Activation by Tα

There are two proposed mechanisms for the activation of PDE. The first proposes that the two inhibitory subunits are differentially bound, sequentially removable and exchangeable between the native complex PDEαβγ₂ and PDEαβ. GTP-bound-Tα removes the inihibitory γ subunits one at a time from the αβ catalytic subunits.^[2] The second and more likely mechanism states that the GTP-Tα complex binds to the γ subunits but rather than dissociating from the catalytic subunits, it stays with the PDEαβ complex.^[3][4] Binding of the GTP-Tα complex to the PDE γ subunits likely causes a conformational shift in the PDE, allowing better access to the site of cGMP hydrolysis on PDEαβ.^[3]

Structure

The binding site for PDE α and β subunits are likely to be in the central region of the PDE γ subunits. The C-terminal of the PDE γ subunit is likely to be involved in inhibition of PDE α and β subunits, the binding site for Tα and GTPase accelerating activity for the GTP-bound Tα.^[4]

In cones, PDE is a homodimer of alpha chains, associated with several smaller subunits. Both rod and cone PDEs catalyze the hydrolysis of cAMP or cGMP to their 5’ monophosphate form. Both enzymes also bind cGMP with high affinity. The cGMP-binding sites are located in the N-terminal half of the protein sequence, while the catalytic core resides in the C-terminal portion.

Examples

Human genes encoding proteins containing this domain include:

• PDE1A, PDE1B, PDE1B2, PDE1C, PDE2A, PDE3A, PDE3B, PDE4A, PDE4B, PDE4B5, PDE4C, PDE4D,
• PDE5A, PDE6A, PDE6B, PDE6C, PDE7A, PDE7B, PDE8A, PDE8B, PDE9A,
• PDE10A, PDE10A2, PDE11A,

References

This article incorporates text from the public domain Pfam and InterPro IPR002073