Reviews of Phosphodiester Bond

What is a Phosphodiester Bond?

In the field of biochemistry, the phosphodiester bond is considered to be a crucial molecular structure widely found in biological molecules such as nucleic acids, including DNA and RNA, as well as adenosine triphosphate, and is also known as the 3’,5’-phosphodiester bond. It is important to note that the phosphodiester bond is a chemical group, not a covalent or ionic bond in the usual chemical sense. This bond can be thought of as being formed by the esterification of one molecule of phosphoric acid with the hydroxyl groups (3'-OH, 5’-OH) of two five-carbon sugar molecules. The process involves the removal of two hydroxyl groups from the phosphoric acid and one hydrogen from each of the 3'-OH and 5'-OH of the two five-carbon sugars, resulting in the formation of a 3',5'-phosphodiester bond. This bond can be hydrolyzed by the action of acids, bases, or enzymes.DNA polymerase, restriction endonucleases (restriction enzymes), DNA ligases, DNA hydrolases, and RNA polymerases all act on the phosphodiester bond. The function of this bond is to link phosphate groups together, forming the basis for the storage and transfer of information in living systems. This bond is unique in that it plays an integral role in the genetic material of the cell. Through the phosphodiester bond, the nucleic acid chain is able to form a double helix structure, enabling the stable transmission of genetic information to future generations.The phosphodiester bond in DNA is extremely stable. At 25°C in a neutral aqueous solution of pH 7.0, its half-life is hundreds of billions of years, which is older than the age of the earth itself. The phosphodiester bond is an indispensable molecular structure whose role is not limited to connecting phosphate groups, but involves key mechanisms for information transfer, biological stability and cytogenetic properties.

Figure 1. Formation of the phosphodiester bond through the condensation reaction. (M, S, Ahmed, 2002)

Classification of Phosphodiester Bond

• Phosphodiester Bonds in Nucleic Acids

Phosphodiester bonds in DNA: In the DNA (deoxyribonucleic acid) molecule, phosphodiester bonds connect deoxyribose molecules to form the well-known DNA double helix structure. These bonds play a key role in the transmission and replication of genetic information.

Phosphodiester bonds in RNA: In RNA (ribonucleic acid), phosphodiester bonds connect ribose molecules to form the nucleic acid chain of the RNA molecule.RNA is involved in biological processes such as protein synthesis, where the phosphodiester bonds play a role in supporting the structure and transmitting information.

• Phosphodiester Bonds in Adenosine Triphosphates

ATP is a key molecule for energy transfer within the cell, in which the phosphodiester bond connects three phosphate groups. The release or transfer of these phosphate groups provides the energy needed by the cell, making ATP the primary molecule for energy storage and transfer in living organisms.

What is Phosphodiesterase?

Phosphodiesterases (PDEs) function to hydrolyze intracellular second messengers such as cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) in order to degrade intracellular cAMP or cGMP and thus terminate the biochemical actions conducted by these second messengers. cAMP and cGMP play important regulatory roles for cellular activities. And the regulation of their concentration is mainly determined by the balance between the synthesis of adenylate cyclase and the hydrolysis of phosphodiesterase.PDEs are a series of hydrolytic enzymes that hydrolyze cAMP and cGMP, which are important in regulating the levels of cAMP and cGMP. cAMP and cGMP are important second messengers in the cell. cAMP is formed from adenosine triphosphate catalyzed by adenylate cyclase, whose degradation is catalyzed by various The degradation of cAMP is catalyzed by different PDEs, which catalyze the hydrolysis of cyclic nucleoside phosphate diester bonds. cGMP degradation is catalyzed by the corresponding PDEs with cGMP activity.

Figure 2. Intracellular signaling and cyclic nucleotide phosphodiesterases. (L, Claire, 2022)

• Types of Phosphodiesterases

A total of 11 isoforms of PDEs have been identified in mammals, including PDE1-PDE11.According to the hydrolytic properties of cAMP and cGMP, these 11 PDE isoforms are classified into three major groups: the first group specifically hydrolyzes cAMP, including PDE4, PDE7, and PDE8.The second group specifically hydrolyzes cGMP, including PDE5, PDE6, and PDE9.The third group is capable of hydrolyzing both cAMP and cGMP, including PDE1, PDE2, PDE3, PDE10, and PDE11. The third group is capable of hydrolyzing both cAMP and cGMP, including PDE1, PDE2, PDE3, PDE10 and PDE11.

• Basic Functions of Phosphodiesterases

PDEs are a superfamily of enzymes, and the human genome encodes 21 PDE genes, which encode more than 100 PDE variant proteins through different mRNA splicing modes and by using different regulatory approaches such as different translation starting points. These proteins have been classified into 11 isozyme families (PDE1-PDE11) based on their sequence similarity, enzyme kinetic characteristics, regulatory properties, cellular tissue distribution, and pharmacological properties. Among them, PDE4, PDE7, and PDE8 selectively hydrolyze cAMP, PDE5, PDE6, and PDE9 selectively hydrolyze cGMP, and PDE1, PDE2, PDE3, PDE10, and PDE11 are not selective for cAMP and cGMP.

What is Phosphodiesterase Inhibitor?

Phosphodiesterase inhibitors can be categorized according to the specific phosphodiesterase they target. There are 11 families of phosphodiesterase and PDE inhibitors. Of these, the most widely used are four phosphodiesterase inhibitors, including phosphodiesterase type 5 inhibitors (PDE5 inhibitors), phosphodiesterase type 4 inhibitors (PDE4 inhibitors), phosphodiesterase type 3 inhibitors (PDE3 inhibitors), and non-specific inhibitors.

• PDE5 Inhibitors

PDE5 inhibitors work by increasing levels of cGMP and specifically target the penis and lungs.PDE5 inhibitors can be used to study erectile dysfunction by inducing smooth muscle relaxation and increasing blood flow to the penis.

• PDE4 Inhibitors

PDE4 inhibitors work by increasing cAMP levels. They specifically target the airways, skin and immune system, as well as the brain.PDE4 inhibitors work by causing airway smooth muscle relaxation, making them useful in the study of lung diseases such as asthma and COPD.

• PDE3 Inhibitors

PDE3 inhibitors work by increasing the levels of cAMP.PDE3 inhibitors are commonly used in cardiovascular disease. In the heart, they help increase the contractility or ability of the heart to beat. They also relax blood vessels and airway smooth muscle, making them useful in the study of heart failure.

• Nonspecific Inhibitors

Non-specific inhibitors work by reducing the destruction of cAMP by any phosphodiesterase.

References

1. M, S, Ahmed. Comparative Studies on Virus X Affecting Potato Plants in Egypt. ResearchGate Logo. 2002.
2. L, Claire. The Complexity and Multiplicity of the Specific cAMP Phosphodiesterase Family: PDE4, Open New Adapted Therapeutic Approaches. Int. J. Mol. Sci. 2022, 23(18): 10616.