Phosphodiesterase

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Phosphodiesterase (PDEs) has the function of hydrolyzing the second messengers in the cell (cAMP, cyclic adenosine monophosphate or cGMP, cyclic guanosine monophosphate), and degrades the intracellular cAMP or cGMP, thereby ending the biochemical effects conducted by these second messengers. cAMP and cGMP play an important role in regulating cell activities. The adjustment of its concentration is mainly determined by the balance between the synthesis of adenylate cyclase and the hydrolysis of phosphodiesterase (PDEs). PDEs are widely distributed in the human body, and their physiological effects involve many research fields. In recent years, as new therapeutic targets, PDEs have attracted wide attention from many scholars and become a new research hotspot. The clinical research of selective PDE 4 and PDE 5 inhibitors has received special attention.

Figure 1. cGMP.

Genotyping

Molecular cloning technology reveals that phosphodiesterases (PDEs) are a large multi-gene family. The development of selective phosphodiesterases inhibitors will open up new ideas for the treatment of many diseases. PDEs are a large family of multiple genes. It includes 11 types and more than 30 types of phosphodiesterase isoenzymes with different substrate specificities, enzyme kinetic characteristics, regulatory characteristics, and cell and subcellular distribution areas. Similar structures contain two functional areas: regulation and catalysis. The amino acid sequences of the catalytic regions of all types of PDEs are more than 75% identical. Show the homology between family members. And determines the specificity of the substrate or inhibitor. PDEs have different substrate specificities: PDE 4, 7, and 8 acts exclusively on cAMP, while PDE 5, 6, and 9 acts selectively on cGMP. PDE3 binds to cAMP and cGMP with similar affinity, but relatively does not hydrolyze cGMP, so it is considered functionally specific to cAMP, and cGMP acts as a negative regulator through competitive binding with enzyme sites.

Classifications

• Phosphodiesterase 1

PDE1 has three isozymes: PDE1A, 1B and 1C, which are coded by different genes. The catalytic activity of PDE1 is regulated by two CaM binding regions, but each isozyme has its unique Ca threshold to be activated. PDE1C can hydrolyze cAMP and cGMP equally, and can down-regulate glucose-stimulated insulin secretion.

• Phosphodiesterase 2

PDE2 shows different tissue and subcellular distribution. Membrane-bound enzymes exist in the brain and heart. The soluble enzymes are found in the liver and platelets. PDE2 is also distributed in T cells. When the antigen receptor is bound, the PDE2 activity of thymocytes is down-regulated.

Figure 2. Structure of Phosphodiesterase 2.

• Phosphodiesterase 3

The two isozymes of human PDE3, PDE3A and PDE3B, are the products of different genes located on chromosomes 12 and 11, respectively. The catalytic regions of PDE3A and PDE3B both contain a different 44 amino acid inserts. The difference of these 44 amino acids not only distinguishes PDE3A and PDE3B from each other, but also distinguishes the catalytic site of PDE3 from other types of PDEs.

Figure 3. Role of PDE3 in cAMP- and cGMP-mediated signal transduction.

• Phosphodiesterase 4

The isozymes of human PDE4 are diverse, divided into 4 subtypes: PDE4A, 4B, 4C and 4D. PDE4 is involved in the hydrolysis of cAMP in a variety of inflammatory cells. Therefore, inhibiting PDE4 can inhibit immune and inflammatory cells.

Figure 4. Phosphodiesterase 4.

• Phosphodiesterase 6

PDE6 is an important enzyme in the light conversion cascade reaction of photoreceptor cells. Its activity is regulated by heterotrimeric G protein. Rod cell PDE6 holoenzyme is a tetrameric protein, which includes two large catalytic subunits α and β and two small γ subunits with PDE6 inhibitory effect.

• Phosphodiesterase 7

PDE7A1 and PDE7A2 are variants in which the same gene is expressed differently. The mRNAs of both are commonly expressed in various tissues. However, protein expression has strict restrictions, suggesting that the functional role of PDE7 makes its protein translation highly regulated. PDE7A1 activity and protein have been found in T lymphocytes. Inhibition of PDE7 may be beneficial to the treatment of certain immune disorders.

Genotyping

Molecular cloning technology reveals that phosphodiesterases(PDEs) are a large multi-gene family. The development of selective phosphodiesterases inhibitors will open up new ideas for the treatment of many diseases. PDEs are a large family of multiple genes. It includes 11 types and more than 30 types of phosphodiesterase isoenzymes with different substrate specificities, enzyme kinetic characteristics, regulatory characteristics, and cell and subcellular distribution areas. Similar structures contain two functional areas: regulation and catalysis. The amino acid sequences of the catalytic regions of all types of PDEs are more than 75% identical. Show the homology between family members. And determines the specificity of the substrate or inhibitor. PDEs have different substrate specificities: PDE 4, 7, and 8 acts exclusively on cAMP, while PDE 5, 6, and 9 acts selectively on cGMP. PDE3 binds to cAMP and cGMP with similar affinity, but relatively does not hydrolyze cGMP, so it is considered functionally specific to cAMP, and cGMP acts as a negative regulator through competitive binding with enzyme sites.

Mechanism

As the second messenger of neurotransmitters, hormones, light and odor, cAMP and cGMP widely act on target organs in cells, such as kinases, ion channels and various PDEs. When external signals are transmitted across the membrane and cause a series of physiological reactions to activate nucleotide cyclase (as shown in Figure 1), cAMP and cGMP are produced. The mission of the PDEs family is to hydrolyze and inactivate them into 5-mono Monophosphate nucleoside5 (AMP). The balance between the synthesis of nucleotide cyclase and the hydrolytic inactivation of PDEs determines the concentration of the second messengers cAMP and cGMP. It is worth noting that cGMP is not only hydrolyzed by PDEs, but also can regulate the activity of some PDEs. For example, PDE2 can be stimulated by cGMP, while PDE3 can be inhibited by cGMP, and PDE4 is not sensitive to cGMP.