Inbiochemistry,phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor[1] or the addition of a phosphate group to a molecule. A common phosphorylating agent (phosphate donor) isATP and a common family of acceptor arealcohols:
This equation can be written in several ways that are nearly equivalent that describe the behaviors of various protonated states of ATP, ADP, and the phosphorylated product.As is clear from the equation, a phosphate group per se is not transferred, but a phosphoryl group (PO3-).Phosphoryl is anelectrophile.[2]This process and its inverse,dephosphorylation, are common inbiology.[3]Protein phosphorylation often activates (or deactivates) manyenzymes.[4][5]
Although most often discussed in terms of theconsumption of ATP (GTP and others), phosphorylation must also be involved in the production of these energy-rich species. ATP is produced by:
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:
Glucose is converted to glucose-6-phosphate catalyzed by the enzymehexokinase. Fructose-6-phosphate is converted tofructose 1,6-bisphosphate. This reaction is catalyzed byphosphofructokinase.
Glyceraldehyde 3-phosphate is again phosphorylated to give1,3-bisphosphoglycerate. This reaction is catalyzed byglyceraldehyde-3-phosphate dehydrogenase (GAPDH).
The phosphorylation of glucose to glucose 6-phosphate has role in regulatingglycogen synthase.
Glucose is phosphorylated to glucose 6-phosphate to allow its transport across the membrane by ATP-D-glucose 6-phosphotransferase and non-specifichexokinase (ATP-D-hexose 6-phosphotransferase).[6][7] 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.[6]
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,[6] 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.[8]
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.[7]
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.[9]
Protein phosphorylation is the most commonpost-translational modification in eukaryotes. The most common phospho-amino acid residues are those serine, threonine, and tyrosine at a ratio of 1800:200:1.[10] Phosphorylation of the side chains of these residues throughphosphoester bond formation, onhistidine,lysine andarginine throughphosphoramidate bonds, and onaspartic acid andglutamic acid through mixedanhydride linkages.
Protein phosphorylation is common on human non-canonical amino acids, including motifs containing phosphorylated histidine, aspartate, glutamate,cysteine, arginine and lysine in HeLa cell extracts.[11] Histidine phosphorylates at both the 1 and 3 N-atoms of theimidazole ring.[12][13] Phospho-tyrosine is much more stable than phospho-serine and -threonine which are in turn more stable than other phospho-amino acids,[10] hence the analysis of phosphorylated histidine (and other non-canonical amino acids) using standard biochemical and mass spectrometric approaches is much more challenging[11][14][15] and special procedures and separation techniques are required for their preservation alongside classical Ser, Thr and Tyr phosphorylation.[16]
The prominent role of protein phosphorylation inbiochemistry is illustrated by the many publication on the subject (as of March 2015, theMEDLINE database returns over 240,000 articles, mostly onprotein phosphorylation).
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