Inbiochemistry,phosphorylation is the attachment of aphosphate group to a molecule or an ion.[1] This process and its inverse,dephosphorylation, are common inbiology.[2]Protein phosphorylation often activates (or deactivates) manyenzymes.[3][4]
Phosphorylation is essential to the processes of bothanaerobic andaerobic respiration, which involve the production ofadenosine triphosphate (ATP), the "high-energy" exchange medium in the cell. During aerobic respiration, ATP is synthesized in themitochondrion by addition of a third phosphate group toadenosine diphosphate (ADP) in a process referred to asoxidative phosphorylation. ATP is also synthesized bysubstrate-level phosphorylation duringglycolysis. ATP is synthesized at the expense of solar energy byphotophosphorylation in thechloroplasts of plant cells.
Phosphorylation ofsugars is often the first stage in theircatabolism. Phosphorylation allows cells to accumulate sugars because the phosphate group prevents the molecules from diffusing back across theirtransporter. Phosphorylation ofglucose is a key reaction in sugar metabolism. The chemical equation for the conversion of D-glucose to D-glucose-6-phosphate in the first step ofglycolysis is given by:
Glycolysis is an essential process of glucose degrading into two molecules ofpyruvate, through various steps, with the help of different enzymes. It occurs in ten steps and proves that phosphorylation is a much required and necessary step to attain the end products. Phosphorylation initiates the reaction instep 1 of the preparatory step[5] (first half of glycolysis), and initiates step 6 of payoff phase (second phase of glycolysis).[6]
Glucose, by nature, is a small molecule with the ability to diffuse in and out of the cell. By phosphorylating glucose (adding a phosphoryl group in order to create a negatively chargedphosphate group[7]), glucose is converted to glucose-6-phosphate, which is trapped within the cell as the cell membrane is negatively charged. This reaction occurs due to the enzymehexokinase, an enzyme that helps phosphorylate many six-membered ring structures. Phosphorylation takes place in step 3, where fructose-6-phosphate is converted tofructose 1,6-bisphosphate. This reaction is catalyzed byphosphofructokinase.
While phosphorylation is performed by ATPs during preparatory steps, phosphorylation during payoff phase is maintained by inorganic phosphate. Each molecule ofglyceraldehyde 3-phosphate is phosphorylated to form1,3-bisphosphoglycerate. This reaction is catalyzed byglyceraldehyde-3-phosphate dehydrogenase (GAPDH). The cascade effect of phosphorylation eventually causes instability and allows enzymes to open the carbon bonds in glucose.
Phosphorylation functions is an extremely vital component of glycolysis, as it helps in transport, control, and efficiency.[8]
Glycogen is a long-term store of glucose produced by the cells of theliver. In theliver, the synthesis ofglycogen is directly correlated with blood glucose concentration. High blood glucose concentration causes an increase in intracellular levels ofglucose 6-phosphate in the liver,skeletal muscle, and fat (adipose) tissue. Glucose 6-phosphate has role in regulatingglycogen synthase.
High blood glucose releasesinsulin, stimulating the translocation of specific glucose transporters to the cell membrane; glucose is phosphorylated to glucose 6-phosphate during transport across the membrane by ATP-D-glucose 6-phosphotransferase and non-specifichexokinase (ATP-D-hexose 6-phosphotransferase).[9][10] Liver cells are freely permeable to glucose, and the initial rate of phosphorylation of glucose is the rate-limiting step in glucose metabolism by the liver.[9]
The liver's crucial role in controlling blood sugar concentrations by breaking down glucose into carbon dioxide and glycogen is characterized by the negativeGibbs free energy (ΔG) value, which indicates that this is a point of regulation with.[clarification needed] The hexokinase enzyme has a lowMichaelis constant (Km), indicating a high affinity for glucose, so this initial phosphorylation can proceed even when glucose levels at nanoscopic scale within the blood.
The phosphorylation of glucose can be enhanced by the binding offructose 6-phosphate (F6P), and lessened by the bindingfructose 1-phosphate (F1P). Fructose consumed in the diet is converted to F1P in the liver. This negates the action of F6P on glucokinase,[11] which ultimately favors the forward reaction. The capacity of liver cells to phosphorylate fructose exceeds capacity to metabolize fructose-1-phosphate. Consuming excess fructose ultimately results in an imbalance in liver metabolism, which indirectly exhausts the liver cell's supply of ATP.[12]
Allosteric activation by glucose-6-phosphate, which acts as an effector, stimulates glycogen synthase, and glucose-6-phosphate may inhibit the phosphorylation of glycogen synthase bycyclic AMP-stimulatedprotein kinase.[10]
Phosphorylation of glucose is imperative in processes within the body. For example, phosphorylating glucose is necessary for insulin-dependentmechanistic target of rapamycin pathway activity within the heart. This further suggests a link between intermediary metabolism and cardiac growth.[13]
Protein phosphorylation is the most abundantpost-translational modification in eukaryotes. Phosphorylation can occur onserine,threonine andtyrosine side chains (in other words, on their residues) throughphosphoester bond formation, onhistidine,lysine andarginine throughphosphoramidate bonds, and onaspartic acid andglutamic acid through mixedanhydride linkages. Recent evidence confirms widespread histidine phosphorylation at both the 1 and 3 N-atoms of theimidazole ring.[14][15] Recent work demonstrates widespread human protein phosphorylation on multiple non-canonical amino acids, including motifs containing phosphorylated histidine, aspartate, glutamate,cysteine, arginine and lysine in HeLa cell extracts.[16] However, due to the chemical lability of these phosphorylated residues, and in marked contrast to Ser, Thr and Tyr phosphorylation, the analysis of phosphorylated histidine (and other non-canonical amino acids) using standard biochemical and mass spectrometric approaches is much more challenging[16][17][18] and special procedures and separation techniques are required for their preservation alongside classical Ser, Thr and Tyr phosphorylation.[19]
The prominent role of protein phosphorylation inbiochemistry is illustrated by the huge body of studies published on the subject (as of March 2015, theMEDLINE database returns over 240,000 articles, mostly onprotein phosphorylation).
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