Dephosphorylation
In
and inorganic phosphate.Dephosphorylation employs a type of hydrolytic enzyme, or
The reversible phosphorylation-dephosphorylation reaction occurs in every physiological process, making proper function of protein phosphatases necessary for organism viability. Because protein dephosphorylation is a key process involved in
History
The discovery of dephosphorylation came from a series of experiments examining the enzyme phosphorylase isolated from rabbit skeletal muscle. In 1955,
Since the discovery of these dephosphorylating proteins, the reversible nature of phosphorylation and dephosphorylation has been associated with a broad range of functional proteins, primarily enzymatic, but also including nonenzymatic proteins.[5] Edwin Krebs and Edmond Fischer won the 1992 Nobel Prize in Physiology or Medicine for the discovery of reversible protein phosphorylation.[6]
Function
Phosphorylation and dephosphorylation of hydroxyl groups belonging to neutral but polar
Post-translational modification
During the synthesis of proteins, polypeptide chains, which are created by ribosomes translating mRNA, must be processed before assuming a mature conformation. The dephosphorylation of proteins is a mechanism for modifying behavior of a protein, often by activating or inactivating an enzyme. Components of the protein synthesis apparatus also undergo phosphorylation and dephosphorylation and thus regulate the rates of protein synthesis.[10]
As part of posttranslational modifications, phosphate groups may be removed from serine, threonine, or tyrosine. As such, pathways of intracellular signal transduction depend on sequential phosphorylation and dephosphorylation of a wide variety of proteins.
ATP
- ATP4− + H2O ⟶ ADP3− + HPO42− + H+
Adenosine triphosphate, or ATP, acts as a free energy "currency" in all living organisms. In a spontaneous dephosphorylation reaction 30.5 kJ/mol is released, which is harnessed to drive cellular reactions. Overall, nonspontaneous reactions coupled to the dephosphorylation of ATP are spontaneous, due to the negative free energy change of the coupled reaction. This is important in driving oxidative phosphorylation. ATP is dephosphorylated to ADP and inorganic phosphate.[11]
On the cellular level, the dephosphorylation of ATPases determines the flow of ions into and out of the cell. Proton pump inhibitors are a class of drug that acts directly on ATPases of the gastrointestinal tract.
Other reactions
Other molecules besides ATP undergo dephosphorylation as part of other biological systems. Different compounds produce different free energy changes as a result of dephosphorylation.[11]
Molecule | Change in Free Energy |
---|---|
Acetyl phosphate | 47.3 kJ/mol |
Glucose-6-phosphate | 13.8 kJ/mol |
Phosphoenolpyruvate (PEP) | -61.9 kJ/mo |
Phosphocreatine | 43.1 kJ/mo |
Psilocybin also relies on dephosphorylation to be metabolized into psilocin and further eliminated. No information on psilocybin's effect on the change in free energy is currently available.
Photosystem II
The first protein complex of the photosynthesis component light-dependent reactions is referred to as photosystem II. The complex utilizes an enzyme to capture photons of light, providing the greater photosynthesis process with all of the electrons needed to produce ATP. Photosystem II is particularly temperature sensitive,[12] and desphosphorylation has been implicated as a driver of plasticity in responding to varied temperature. Accelerated protein dephosphorylation in photosynthetic thylakoid membranes occurs at elevated temperatures, directly impacting the desphosphorylation of key proteins within the photosystem II complex.[13]
Pathology
Excessive dephosphorylation of the membrane ATPases and proton pumps in the gastrointestinal tract leads to higher secretory rates of caustic peptic acids. These result in heartburn and esophagitis. In combination with Helicobacter pylori infection, peptic ulcer disease is caused by the elevated pH dephosphorylation elicits.[14]
The microtubule-associated protein tau is abnormally hyperphosphorylated when isolated from the brain of patients who suffer from Alzheimer's disease. This is due to the dysfunction of dephosphorylation mechanisms at specific amino acids on the tau protein. Tau dephosphorylation is catalysed by protein phosphatase-2A and phosphatase-2B. Deficiency or modification of one or both proteins may be involved in abnormal phosphorylation of tau in Alzheimer's disease[15]
Dephosphorylation has also been linked to
Research has also suggested that modifications to dephosphorylation impact physiological processes implicated in
Treatment
Inhibition of proton pumps[14] significantly decreases the acidity of the gastrointestinal tract, reducing the symptoms of acid-related diseases. The resulting change in pH decreases survival of the bacteria H.pylori, a major cause of peptic ulcer disease. Once the proton pump inhibitor eradicates this bacteria within the gut, reversing erosive reflux. Treating heart disease has improved with the use of drugs that inhibit AMPK via dephosphorylation.[18] In the treatment of diabetes, sulfonylurea drugs are able to stimulate dephosphorylation of the glucose transporter GLUT4, decreasing insulin resistance and increasing and glucose utilization.[19]
Research applications
Dephosphorylation can play a key role in molecular biology, particularly
Underlying evolutionary forces
The natural selection power for dephosphorylation is less understood. A recent study has found that IRF9, which is from the interferon-regulatory factors family (IRFs), a critical family for anti-viral immune response, could be influenced by natural selection during Human species evolution.[22] The positive selection has been found on the amino acid site Val129 (NP_006075.3:p.Ser129Val) of human IRF9. The ancestral state (Ser129) is conserved among mammals, while the novel state (Val129) was fixed before the "out-of-Africa" event ~ 500,000 years ago. This young amino acid (Val129) may serve as a dephosphorylation site of IRF9. The dephosphorylation may affect the immune activity of IRF9.[22]
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