Why is glucokinase not inhibited by g6p

An interesting discovery is that some of the enzymes of glucose catabolism in malignant cancer cells occur as their fetal, not adult, isozymes. The fine-tuning of metabolic rates through the different responses of isozyme forms to allosteric modulators.

Hexokinase D glucokinase of liver and the hexokinase isozymes found in other tissues differ in their sensitivity to inhibition by their product, glucosephosphate p. In vertebrates there are at least three isozymes of pyruvate kinase, differing somewhat in their tissue distribution and in their response to modulators. High concentrations of ATP inhibit pyruvate kinase allosterically, by decreasing the affinity of the enzyme for its substrate phosphoenolpyruvate PEP.

The level of PEP normally found in cells is not high enough to saturate the enzyme, and the reaction rate will accordingly be low at normal PEP concentrations. Pyruvate kinase is also inhibited by acetyl-CoA and by long-chain fatty acids, both important fuels for the citric acid cycle.

Recall that acetyl-CoA acetate is produced by the catabolism of fats and amino acids, as well as by glucose catabolism; see Fig. Because the citric acid cycle is a major source of energy for ATP production, the availability of these other fuels reduces the dependence on glycolysis for ATP. Thus, whenever the cell has a high concentration of ATP, or whenever ample fuels are already available for energy-yielding respiration, glycolysis is inhibited by the slowed action of pyruvate kinase.

The result is a high steadystate concentration of ATP. Citrate the ionized form of citric acid , a key intermediate in the aerobic oxidation of pyruvate Chapter 15 , also serves as an allosteric regulator of PFK-1; high citrate concentration increases the inhibitory effect of ATP, further reducing the flow of glucose through glycolysis. In this case, as in several others to be encountered later, citrate serves as an intracellular signal that the cell's needs for energy-yielding metabolism and for biosynthetic intermediates are being met.

The most significant allosteric regulator of PFK-1 is fructose-2,6bisphosphate, which, as noted earlier, strongly activates the enzyme. The concentration of fructose-2,6-bisphosphate in liver decreases in response to the hormone glucagon, slowing glycolysis and stimulating glucose synthesis in liver. Figure a A ribbon diagram of E. Each subunit has its own catalytic site and its own binding sites for the allosteric activators.

At low concentrations of ATP the K 0. At high ATP, K 0. Figure The reaction in gluconeogenesis that bypasses the irreversible phosphofructokinase-1 reaction in glycolysis. The conversion of fructose-1,6bisphosphate to fructosephosphate is catalyzed by fructose-1,6-bisphosphatase called FBPase-1 to distinguish it from a similar enzyme described in Chapter To prevent futile cycling in which glucose is simultaneously degraded by glycolysis and resynthesized by gluconeogenesis Chapter 19 , the enzymes unique to each pathway are reciprocally regulated by common allosteric effectors.

During hyperglycemic condition insulin is released which trigger the synthesis of glucokinase. GKRP-glucokinase complex moves to nucleus of liver and the phosphorylation of glucose into glucose 6 phosphate is prevented as this reaction occur in cytoplasm. The complex formation is trigger in high concentration of fructosephosphate.

When blood glucose levels rise after a meal, GKRP releases glucokinase caused by exchange with fructosephosphate , and glucokinase moves back through the nuclear pores and can again phosphorylate glucose. Regulation of PFK1. PFK-1 has a homotetrameric enzyme composed of four identical subunits. Like other allosteric proteins hemoglobin and enzymes ATCase the binding of allosteric effectors and substrates is communicated to each of the active sites.

PFK exist in two state of conformations, called the T and R states. These two conformational states are in equilibrium:. AMP in the cell is formed by the enzyme adenylate kinase. The function of the glycolytic pathway is to generate ATP. ATP is both a substrate and an allosteric inactivator. The enzyme has two binding sites for ATP. One is the substrate binding site and the other one is an inhibitory site. The other substrate fructosephosphate binds only to the R state.

High concentrations of ATP shift the equilibrium towards the T conformation which decreases the affinity of the enzyme for FP. Fructose-1,6-bisphosphatase is another important site of gluconeogenesis regulation. Allosteric effectors of fructose-1, 6-bisphosphatase and Phosphofructokinase are common. These effectors reciprocally regulate both enzymes.

Fructose 1,6-bisphosphatase : gluconeogenesis, irreversible. The two enzymes are reciprocally regulated or ATP would be lost without energy conservation. Prevents futile cycling like using a stationary bike.

Fructose-2,6-bisphosphate :. Breakdown: Fructose-2,6 bisphosphatase FBPase A hexokinase is an enzyme that phosphorylates a six-carbon sugar, a hexose, to a hexose phosphate. In most tissues and organisms, glucose is the most important substrate of hexokinases, and glucose 6-phosphate the most important product. Hexokinases have been found in every organism checked, ranging from bacteria, yeast, and plants, to humans and other vertebrates.

They are categorized as actin fold proteins, sharing a common ATP binding site core surrounded by more variable sequences that determine substrate affinities and other properties.

Several hexokinase isoforms or isozymes providing different functions can occur in a single species. Little is known about the regulatory characteristics of this isoform.

Hexokinase Structure: The tertiary structure of hexokinase includes an. There is a large amount of variation associated with this structure. The ATP-binding domain is composed of five beta sheets and three alpha helices. The crevice indicates the ATP-binding domain of this glycolytic enzyme.

The molecular weights of hexokinases are around kD. Each consists of two similar 50kD halves, but only in hexokinase II do both halves have functional active sites.

Mechanism of Hexokinase: In the first reaction of glycolysis, the gamma-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 of glucose. This step is a direct nucleophilic attack of the hydroxyl group on the terminal phosphoryl group of the ATP molecule. This produces glucosephosphate and ADP [1]. Hexokinase is the enzyme that catalyzes this phosphoryl group transfer. Hexokinase undergoes and induced-fit conformational change when it binds to glucose, which ultimately prevents the hydrolysis of ATP.

It is also allosterically inhibited by physiological concentrations of its immediate product, glucosephosphate. This is a mechanism by which the influx of substrate into the glycolytic pathway is controlled. These residues are located in the deep cleft at the interface between the two lobes. This active site is capable of bonding two ligands, glucose, and glucosephosphate.