Fructokinase liver

Genetic deficiency of fructokinase is benign and often detected incidentally when the urine is checked for glucose with a dipstick. Fructose 1-phosphate aldolase deficiency is a severe disease because of accumulation of fructose 1-phosphate in the liver and renal proximal tubules. Table 1-12-4 compares the two conditions. Symptoms are reversed after removing fructose and sucrose from the diet. 

Figure 11.2 Pathway for conversion of fructose to acetyl-CoA. The enzyme fructokinase phosphorylates fructose to form fructose 1-phosphate. (The enzyme is present only in the liver.) Fructose 1-phosphate is cleaved by aldolase to form glyceraldehyde and dihydroxyacetone phosphate. Glyceraldehyde is phos-phorylated to form glyceraldehyde 3-phosphate, catalysed by the enzyme triokinase. Dihydroxyacetone phosphate is converted to glyceraldehyde 3-phosphate, catalysed by the isomerase. Glyceraldehyde 3-phosphate is converted to pyruvate by the glycolytic reactions (Chapter 6).

In the liver, the enzyme fructokinase catalyzes the reaction of fructose with ATP to form fmctose 1 -phosphate. 

This is a major pathway of fructose entry into glycolysis in the muscles and kidney. In the liver, however, fructose enters by a different pathway. The liver enzyme fructokinase catalyzes the phosphorylation of fructose at C-l rather than C-6 ... 

Enzymes required for fructose to enter intermediary metabolism, Fructose is first phosphorylated to fructose 1-phosphate by fructokinase, and then cleaved by aldolase B to dihydroxyacetone phosphate and glyceraldehyde. These enzymes are found in the liver, kidney, and small intestinal mucosa. 

Cause and treatment of hereditary fructose intolerance A deficiency of fructokinase causes a benign condition, but a deficiency of aldolase B causes hereditary fructose intolerance, in which severe hypoglycemia and liver damage can lead to death if the amount of fructose (and, therefore, sucrose) in the diet are not severely limited. 

Reinhart, G. D. (1980). Influence of polyethylene glycols on the kinetics of rat liver phospho-fructokinase. J. Biol. Chem. 255 10576-10578. 

DHAP is a glycolysis intermediate, whereas glyceraldehyde must be reduced by a mitochondrial enzyme, glyceraldehyde dehydrogenase, to glycerol, which is then subject to action by glycerol kinase in the liver. The aldolase seems to be the principal pathway of metabolizing fructose and depends on the initial phosphorylation step catalyzed by fructokinase, which produces fructose-l-phosphate. Fructokinase is defective in an inherited disorder, essential fructosuria. Fructose-l-phosphate aldolase is deficient in the hereditary disorder fructose intolerance. 

Positive allosteric activators of phospho-fructokinase 1 in the liver include... 

In the liver, kidney, and intestine, fructose can be converted to glycolytic/ gluconeogenic intermediates by the actions of three enzymes—fructokinase, aldolase B, and triokinase (also called triose kinase)—as shovra in Figure 24-1. In these tissues, fructose is rapidly phosphorylated to fructose 1-phosphate (FIP) by fructokinase at the expense of a molecule of adenosine triphosphate (ATP). This has the effect of trapping fructose inside the cell. A deficiency in this enzyme leads to the rare but benign condition known as essential fmcto-suria. In other tissues such as muscle, adipose, and red blood cells, hexokinase can phosphorylate fructose to the glycolytic intermediate fmctose 6-phosphate (F6P). 

Liver is the principal site of D-fructose metabolism. D-Fructose is transported to the liver from the small intestine by way of the portal blood-vessel. Experiments with perfused pig and rat livers revealed that the rate of elimination of D-fructose from blood is a function of the sugar concentration,26,27 and follows Michaelis-Menten kinetics.27,28 Carrier-mediated, liver-membrane transport of D-fructose has a high29 Km and Vmax, in comparison to the intracellular phosphorylation constants of D-fructose in both pigeon and rat livers.27,28 For example, the calculated rat-liver transport for D-fructose has a Km of 67 mM and a Vmax of 30 /u,mole.min. g-1, in contrast to the lower, calculated fruc-tokinase Km of 1.0 mM and Vmax of 10.3 pmole. min r1. g 1 with D-fruc-tose and Km of 0.54 mM with adenosine 5 -triphosphate (ATP). In perfused pig-liver,28 the transport Km for D-fructose is only ten times that of intracellular phosphorylation by fructokinase. Hence, D-fructose-transport values suggested that, at physiological D-fructose concentrations, membrane transport limits the rate of uptake, thereby protecting the liver from severe depletion of adenine nucleotide.28,29... 

Liver metabolizes up to 85% of orally administered D-fructose. Fructokinase, aldolase, and triose kinase are important control enzymes for hepatic D-fructose metabolism.62 The activities of these enzymes are subject to dietary composition and hormonal control. Total fructokinase, aldolase, and triose kinase decrease to about half or less of their normal activity on fasting for 48 to 72 hours, and are restored to normal in 24 hours upon D-fructose administration. Longterm feeding of D-fructose results in the maintenance of a considerably higher level of all three enzymes, an effect also seen with rats maintained on a high-fat or high-protein diet.62... 

Fructokinase is found in liver,56,312-315 kidney,32 intestinal mucosa,33,316 adipose tissue,71,72 and lenses,317 but not in heart muscle, skeletal muscle, brain, and seminal vesicles.57... 

Fructose is phosphorylated primarily in the liver via fructokinase to form fructose-1-phosphate. Fructose can also be phosphorylated by the various hexokinases that catalyze formation of fructose-6-phosphate. However, the Km values of these enzymes for fructose are extremely high, whereas the Km values for glucose are orders of magnitude lower. Therefore, these hexokinases do not catalyze appreciable phosphorylation of fructose, especially in the presence of 5 mM glucose, the normal concentration in blood (Fig. 12.7). 

There are two genetic diseases associated with fructose metabolism. One is fructosuria, in which the liver enzyme, fructokinase, is missing. Thus, fructose is not metabolized but, instead, accumulates in the blood and is passed into... 

In vertebrate liver, the enzyme fructokinase phosphorylates fructose to fructose- 1-phosphate (FIP). FIP is then cleaved by a specific enzyme, aldolase B to dihydroxyacetone phosphate (DHAP), a glycolytic intermediate, and D-glyceraldehyde (see below). The latter is then phosphorylated in an ATP-dependent reaction to give the glycolytic intermediate glyceraldehyde-3-phosphate. 

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