In enzymology,1-phosphofructokinase (PFK1) (EC 22.214.171.124) is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are ATP and D-fructose 1-phosphate, whereas its two products are ADP and D-fructose 1,6-bisphosphate.
This enzyme belongs to the family of transferases, specifically those transferring phosphorus-containing groups (phosphotransferases) with an alcohol group as acceptor. The systematic name of this enzyme class is ATP:D-fructose-phosphate 6-phosphotransferase. Other names in common use include fructose-1-phosphate kinase, 1-phosphofructokinase (phosphorylating), D-fructose-1-phosphate kinase, fructose 1-phosphate kinase, and 1-phosphofructokinase. This enzyme participates in fructose and mannose metabolism.
As of late 2007, only one structure has been solved for this class of enzymes, with the PDB accession code 2JG5.
1-Phosphofructokinase is a tetramer of 4 identical subunits that each have a catalytic site. In addition to the catalytic binding sites, there are 4 additional binding sites for allosteric regulation.
1-phosphofructokinase catalyzes the committed step of glycolysis. This step is considered the rate limiting step of glycolysis, and ultimately determines the rate of glucose oxidation in the cell. This reaction is a phosphoryl group transfer from ATP to fructose 6-phosphate, yielding fructose 1,6-biphosphate. The reaction is highly exergonic and is irreversible within the cell, though can be bypassed in gluconeogenesis via the enzyme fructose 1,6-bisphosphatase.
The regulation of 1-phosphofructokinase occurs primarily by allosteric effectors, and is based on the cell's energy needs. There are two ATP binding sites; a substrate site where the phosphate transfer occurs, and an allosteric site where allosteric regulation occurs. ATP acts as an allosteric inhibitor and when cellular concentrations of ATP are high, and the cell's energy needs are low, the reaction catalyzed by 1-phosphofructokinase is inhibited. When the cell is actively consuming ATP and stores deplete, the concentration of ATP lowers while the concentrations of AMP and ADP increase. AMP and ADP are both positive effectors of 1-phosphofructokinase and bind allosterically to activate the reaction. This activation encourages glycolysis and ATP production. Inhibition can also occur via citrate, a product of glycolysis and intermediate in the citric acid cycle. An increased concentration of citrate indicates the cell is meeting current energy needs, and therefore encourages allosteric inhibition of 1-phosphofructokinase allosterically via ATP.
Allosteric regulation of 1-phosphofructokinase is facilitated hormonally to help the liver to maintain blood glucose levels. This is achieved in part by increasing or decreasing rates of glycolysis. When blood glucose levels are low, the secretion of glucagon leads to the phosphorylation of phosphofructokinase 2 which inhibits formation of fructose 2,6-bisphosphate. Therefore when glucagon inhibits phosphofructokinase 2, cellular levels of fructose 2,6-bisphosphate decrease, and reduce activation of 1-phosphofructokinase, ultimately reducing the rate of glycolysis within the cell. When 1-phosphofructokinase is inhibited, rates of gluconeogenesis increase, further aiding an increase in blood sugar. When blood sugar is high, however, the secretion of insulin produces the opposite effect by removing the phosphate group from phosphofructokinase 2, which leads to activation, and formation of fructose 2,6-bisphosphate. As concentrations of fructose 2,6-bisphosphate increase, 1-phosphofructokinase is allosterically activated, and rates of glycolysis increase, consuming glucose. At the same time the rate of gluconeogenesis decrease, also contributing to lowering blood sugar levels.
A deficiency of 1-phosphofructokinase can be inherited due to the genetic disorder glycogenosis type VII Tarui's disease. Research has shown that this disease can lead to insulin resistance and reduced insulin secretion by beta cells in the pancreas, leading to non-insulin-dependent diabetes mellitus, or diabetes type 2. Non-insulin-dependent diabetes mellitus is considered a global epidemic by the World Health Organization.