Dephosphorylation

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In biochemistry, dephosphorylation is the removal of a phosphate (PO3−4) group from an organic compound by hydrolysis. It is a reversible post-translational modification. Dephosphorylation and its counterpart, phosphorylation, activate and deactivate enzymes by detaching or attaching phosphoric esters and anhydrides. A notable occurrence of dephosphorylation is the conversion of ATP to ADP and inorganic phosphate.

Contents

Dephosphorylation employs a type of hydrolytic enzyme, or hydrolase, which cleaves ester bonds. The prominent hydrolase subclass used in dephosphorylation is phosphatase, which removes phosphate groups by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl (–OH) group.

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 cell signalling, [1] protein phosphatases are implicated in conditions such as cardiac disease, diabetes, and Alzheimer's disease. [2]

History

The discovery of dephosphorylation came from a series of experiments examining the enzyme phosphorylase isolated from rabbit skeletal muscle. In 1955, Edwin Krebs and Edmond Fischer used radiolabeled ATP to determine that phosphate is added to the serine residue of phosphorylase to convert it from its b to a form via phosphorylation. [3] Subsequently, Krebs and Fischer showed that this phosphorylation is part of a kinase cascade. Finally, after purifying the phosphorylated form of the enzyme, phosphorylase a, from rabbit liver, ion exchange chromatography was used to identify phosphoprotein phosphatase I and II. [4]

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

Crystallographic structure of human phosphatase and tensin homolog (PTEN). The active site of the blue N-terminal phosphatase domain is shown in yellow. The C-terminal C2 domain is shown in red. Pten.jpg
Crystallographic structure of human phosphatase and tensin homolog (PTEN). The active site of the blue N-terminal phosphatase domain is shown in yellow. The C-terminal C2 domain is shown in red.

Phosphorylation and dephosphorylation of hydroxyl groups belonging to neutral but polar amino acids such as serine, threonine, and tyrosine within specific target proteins is a fundamental part of the regulation of every physiologic process. Phosphorylation involves the covalent modification of the hydroxyl with a phosphate group through the nucleophilic attack of the alpha phosphate in ATP by the oxygen in the hydroxyl. Dephosphorylation involves removal of the phosphate group through a hydration reaction by addition of a molecule of water and release of the original phosphate group, regenerating the hydroxyl. Both processes are reversible and either mechanism can be used to activate or deactivate a protein. Phosphorylation of a protein produces many biochemical effects, such as changing its conformation to alter its binding to a specific ligand to increase or reduce its activity. Phosphorylation and dephosphorylation can be used on all types of substrates, such as structural proteins, enzymes, membrane channels, signaling molecules, and other kinases and phosphatases. The sum of these processes is referred to as phosphoregulation. [8] The deregulation of phosphorylation can lead to disease. [9]

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− + HPO2−4 + 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]

MoleculeChange in free energy
Acetyl phosphate47.3 kJ/mol
Glucose-6-phosphate13.8 kJ/mol
Phosphoenolpyruvate (PEP)−61.9 kJ/mol
Phosphocreatine43.1 kJ/mol

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 cardiac disease, particularly the alteration of actin-myosin interactions that are key for providing the underlying force of a heartbeat. Dephosphorylation is a key part of the myosin cycling kinetics that directly control the actin-myosin interactions. When the dephosphorylation process is interrupted, calcium dependent cardiac contraction is impaired or fully disabled. [16]

Research has also suggested that modifications to dephosphorylation impact physiological processes implicated in Diabetes mellitus. The kinetics of dephosphorylation of insulin receptor substrate-1/2, Akt, and ERK1/2, phosphoproteins are shown to be involved in insulin receptor signaling, and in vitro models demonstrate that changes to dephosphorylation kinetics impact upstream and downstream insulin stimulation. [17]

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 cloning using restriction enzymes. The cut ends of a vector may re-ligate during a ligation step due to phosphorylation. By using a desphosphorylating phosphatase, re-ligation can be avoided. [20] Alkaline phosphatases, which remove the phosphate group present at the 5′ terminus of a DNA molecule, are often sourced naturally, most commonly from calf intestine, and are abbreviated as CIP. [21]

Underlying evolutionary forces

The ancestral state reconstruction and cross-species orthologous alignment. a Ancestral state reconstruction for human Val129 (red arrow) based on the Maximum Parsimony (MP) method in MEGA11. b Regional alignment comprising the human Val129 site (black arrow above the alignment). Anestral state.webp
The ancestral state reconstruction and cross-species orthologous alignment. a Ancestral state reconstruction for human Val129 (red arrow) based on the Maximum Parsimony (MP) method in MEGA11. b Regional alignment comprising the human Val129 site (black arrow above the alignment).

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]

See also

Related Research Articles

<span class="mw-page-title-main">Adenosine triphosphate</span> Energy-carrying molecule in living cells

Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known forms of life, it is often referred to as the "molecular unit of currency" for intracellular energy transfer.

<span class="mw-page-title-main">Glycolysis</span> Series of interconnected biochemical reactions

Glycolysis is the metabolic pathway that converts glucose into pyruvate and, in most organisms, occurs in the liquid part of cells. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

<span class="mw-page-title-main">Metabolism</span> Set of chemical reactions in organisms

Metabolism is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the conversion of food to building blocks of proteins, lipids, nucleic acids, and some carbohydrates; and the elimination of metabolic wastes. These enzyme-catalyzed reactions allow organisms to grow and reproduce, maintain their structures, and respond to their environments. The word metabolism can also refer to the sum of all chemical reactions that occur in living organisms, including digestion and the transportation of substances into and between different cells, in which case the above described set of reactions within the cells is called intermediary metabolism.

A protein phosphatase is a phosphatase enzyme that removes a phosphate group from the phosphorylated amino acid residue of its substrate protein. Protein phosphorylation is one of the most common forms of reversible protein posttranslational modification (PTM), with up to 30% of all proteins being phosphorylated at any given time. Protein kinases (PKs) are the effectors of phosphorylation and catalyse the transfer of a γ-phosphate from ATP to specific amino acids on proteins. Several hundred PKs exist in mammals and are classified into distinct super-families. Proteins are phosphorylated predominantly on Ser, Thr and Tyr residues, which account for 79.3, 16.9 and 3.8% respectively of the phosphoproteome, at least in mammals. In contrast, protein phosphatases (PPs) are the primary effectors of dephosphorylation and can be grouped into three main classes based on sequence, structure and catalytic function. The largest class of PPs is the phosphoprotein phosphatase (PPP) family comprising PP1, PP2A, PP2B, PP4, PP5, PP6 and PP7, and the protein phosphatase Mg2+- or Mn2+-dependent (PPM) family, composed primarily of PP2C. The protein Tyr phosphatase (PTP) super-family forms the second group, and the aspartate-based protein phosphatases the third. The protein pseudophosphatases form part of the larger phosphatase family, and in most cases are thought to be catalytically inert, instead functioning as phosphate-binding proteins, integrators of signalling or subcellular traps. Examples of membrane-spanning protein phosphatases containing both active (phosphatase) and inactive (pseudophosphatase) domains linked in tandem are known, conceptually similar to the kinase and pseudokinase domain polypeptide structure of the JAK pseudokinases. A complete comparative analysis of human phosphatases and pseudophosphatases has been completed by Manning and colleagues, forming a companion piece to the ground-breaking analysis of the human kinome, which encodes the complete set of ~536 human protein kinases.

<span class="mw-page-title-main">Kinase</span> Enzyme catalyzing transfer of phosphate groups onto specific substrates

In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. As a result, kinase produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.

<span class="mw-page-title-main">Phosphorylation</span> Chemical process of introducing a phosphate

In biochemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology. Protein phosphorylation often activates many enzymes.

<span class="mw-page-title-main">Adenosine diphosphate</span> Chemical compound

Adenosine diphosphate (ADP), also known as adenosine pyrophosphate (APP), is an important organic compound in metabolism and is essential to the flow of energy in living cells. ADP consists of three important structural components: a sugar backbone attached to adenine and two phosphate groups bonded to the 5 carbon atom of ribose. The diphosphate group of ADP is attached to the 5’ carbon of the sugar backbone, while the adenine attaches to the 1’ carbon.

Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Pyruvate kinase</span> Class of enzymes

Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyruvate kinase was inappropriately named before it was recognized that it did not directly catalyze phosphorylation of pyruvate, which does not occur under physiological conditions. Pyruvate kinase is present in four distinct, tissue-specific isozymes in animals, each consisting of particular kinetic properties necessary to accommodate the variations in metabolic requirements of diverse tissues.

<span class="mw-page-title-main">Phosphatase</span> Enzyme which catalyzes the removal of a phosphate group from a molecule

In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid monoester into a phosphate ion and an alcohol. Because a phosphatase enzyme catalyzes the hydrolysis of its substrate, it is a subcategory of hydrolases. Phosphatase enzymes are essential to many biological functions, because phosphorylation and dephosphorylation serve diverse roles in cellular regulation and signaling. Whereas phosphatases remove phosphate groups from molecules, kinases catalyze the transfer of phosphate groups to molecules from ATP. Together, kinases and phosphatases direct a form of post-translational modification that is essential to the cell's regulatory network.

<span class="mw-page-title-main">Edwin G. Krebs</span> American biochemist (1918–2009)

Edwin Gerhard Krebs was an American biochemist. He received the Albert Lasker Award for Basic Medical Research and the Louisa Gross Horwitz Prize of Columbia University in 1989 together with Alfred Gilman and, together with his collaborator Edmond H. Fischer, was awarded the Nobel Prize in Physiology or Medicine in 1992 for describing how reversible phosphorylation works as a switch to activate proteins and regulate various cellular processes.

<span class="mw-page-title-main">Glycogen phosphorylase</span> Class of enzymes

Glycogen phosphorylase is one of the phosphorylase enzymes. Glycogen phosphorylase catalyzes the rate-limiting step in glycogenolysis in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond. Glycogen phosphorylase is also studied as a model protein regulated by both reversible phosphorylation and allosteric effects.

<span class="mw-page-title-main">Phosphofructokinase 2</span> Class of enzymes

Phosphofructokinase-2 (6-phosphofructo-2-kinase, PFK-2) or fructose bisphosphatase-2 (FBPase-2), is an enzyme indirectly responsible for regulating the rates of glycolysis and gluconeogenesis in cells. It catalyzes formation and degradation of a significant allosteric regulator, fructose-2,6-bisphosphate (Fru-2,6-P2) from substrate fructose-6-phosphate. Fru-2,6-P2 contributes to the rate-determining step of glycolysis as it activates enzyme phosphofructokinase 1 in the glycolysis pathway, and inhibits fructose-1,6-bisphosphatase 1 in gluconeogenesis. Since Fru-2,6-P2 differentially regulates glycolysis and gluconeogenesis, it can act as a key signal to switch between the opposing pathways. Because PFK-2 produces Fru-2,6-P2 in response to hormonal signaling, metabolism can be more sensitively and efficiently controlled to align with the organism's glycolytic needs. This enzyme participates in fructose and mannose metabolism. The enzyme is important in the regulation of hepatic carbohydrate metabolism and is found in greatest quantities in the liver, kidney and heart. In mammals, several genes often encode different isoforms, each of which differs in its tissue distribution and enzymatic activity. The family described here bears a resemblance to the ATP-driven phospho-fructokinases; however, they share little sequence similarity, although a few residues seem key to their interaction with fructose 6-phosphate.

<span class="mw-page-title-main">Glycogen synthase</span> Enzyme class, includes all types of glycogen/starch synthases

Glycogen synthase is a key enzyme in glycogenesis, the conversion of glucose into glycogen. It is a glycosyltransferase that catalyses the reaction of UDP-glucose and n to yield UDP and n+1.

<span class="mw-page-title-main">Phosphorylase kinase</span>

Phosphorylase kinase (PhK) is a serine/threonine-specific protein kinase which activates glycogen phosphorylase to release glucose-1-phosphate from glycogen. PhK phosphorylates glycogen phosphorylase at two serine residues, triggering a conformational shift which favors the more active glycogen phosphorylase "a" form over the less active glycogen phosphorylase b.

<span class="mw-page-title-main">PRKACA</span> Protein-coding gene in the species Homo sapiens

The catalytic subunit α of protein kinase A is a key regulatory enzyme that in humans is encoded by the PRKACA gene. This enzyme is responsible for phosphorylating other proteins and substrates, changing their activity. Protein kinase A catalytic subunit is a member of the AGC kinase family, and contributes to the control of cellular processes that include glucose metabolism, cell division, and contextual memory. PKA Cα is part of a larger protein complex that is responsible for controlling when and where proteins are phosphorylated. Defective regulation of PKA holoenzyme activity has been linked to the progression of cardiovascular disease, certain endocrine disorders and cancers.

<span class="mw-page-title-main">Myosin-light-chain phosphatase</span>

Myosin light-chain phosphatase, also called myosin phosphatase (EC 3.1.3.53; systematic name [myosin-light-chain]-phosphate phosphohydrolase), is an enzyme (specifically a serine/threonine-specific protein phosphatase) that dephosphorylates the regulatory light chain of myosin II:

<span class="mw-page-title-main">Phosphatidate phosphatase</span>

The enzyme phosphatidate phosphatase (PAP, EC 3.1.3.4) is a key regulatory enzyme in lipid metabolism, catalyzing the conversion of phosphatidate to diacylglycerol:

<span class="mw-page-title-main">Protein phosphorylation</span> Process of introducing a phosphate group on to a protein

Protein phosphorylation is a reversible post-translational modification of proteins in which an amino acid residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Phosphorylation alters the structural conformation of a protein, causing it to become activated, deactivated, or otherwise modifying its function. Approximately 13,000 human proteins have sites that are phosphorylated.

References

  1. ↑ Ardito F, Giuliani M, Perrone D, Troiano G, Lo Muzio L (August 2017). "The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review)". International Journal of Molecular Medicine. 40 (2): 271–280. doi: 10.3892/ijmm.2017.3036 . PMC   5500920 . PMID   28656226.
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  3. ↑ Fischer EH, Krebs EG (September 1955). "Conversion of phosphorylase b to phosphorylase a in muscle extracts". The Journal of Biological Chemistry. 216 (1): 121–132. doi: 10.1016/S0021-9258(19)52289-X . PMID   13252012.
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  10. ↑ Celis JE, Madsen P, Ryazanov AG (June 1990). "Increased phosphorylation of elongation factor 2 during mitosis in transformed human amnion cells correlates with a decreased rate of protein synthesis". Proceedings of the National Academy of Sciences of the United States of America. 87 (11): 4231–4235. Bibcode:1990PNAS...87.4231C. doi: 10.1073/pnas.87.11.4231 . PMC   54082 . PMID   2349232.
  11. 1 2 Casiday R, Herman C, Frey R (5 September 2008). "Energy for the Body: Oxidative Phosphorylation". Department of Chemistry, Washington University. Retrieved 5 April 2013.
  12. ↑ Yamauchi, Yasuo (29 July 2011). "Plants switch photosystem at high temperature to protect photosystem II". Nature Precedings. doi: 10.1038/npre.2011.6168.1 .
  13. ↑ Rokka A, Aro EM, Herrmann RG, Andersson B, Vener AV (August 2000). "Dephosphorylation of photosystem II reaction center proteins in plant photosynthetic membranes as an immediate response to abrupt elevation of temperature". Plant Physiology. 123 (4): 1525–1536. doi:10.1104/pp.123.4.1525. PMC   59108 . PMID   10938368.
  14. 1 2 Robinson M (June 2005). "Proton pump inhibitors: update on their role in acid-related gastrointestinal diseases". International Journal of Clinical Practice. 59 (6): 709–715. doi: 10.1111/j.1368-5031.2005.00517.x . PMID   15924600. S2CID   41914054.
  15. ↑ Gong CX, Grundke-Iqbal I, Iqbal K (August 1994). "Dephosphorylation of Alzheimer's disease abnormally phosphorylated tau by protein phosphatase-2A". Neuroscience. 61 (4): 765–772. doi:10.1016/0306-4522(94)90400-6. PMID   7838376. S2CID   39662308.
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  19. ↑ Müller G, Wied S (December 1993). "The sulfonylurea drug, glimepiride, stimulates glucose transport, glucose transporter translocation, and dephosphorylation in insulin-resistant rat adipocytes in vitro" (PDF). Diabetes. 42 (12): 1852–1867. doi:10.2337/diabetes.42.12.1852. PMID   8243832.
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  22. 1 2 Chen J, He X, Jakovlić I (November 2022). "Positive selection-driven fixation of a hominin-specific amino acid mutation related to dephosphorylation in IRF9". BMC Ecology and Evolution. 22 (1): 132. doi: 10.1186/s12862-022-02088-5 . PMC   9650800 . PMID   36357830. CC-BY icon.svg Text was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.
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