Human Biochemistry, Volume 1 - Murray R. 1993

Bioenergetics and Metabolism of Carbohydrates and Lipids
Metabolism of Major Hexoses
Fructose Metabolism

Fructose can be phosphorylated to yield fructose-6-phosphate in a reaction catalyzed by hexokinase, an enzyme that also catalyzes the phosphorylation of glucose and mannose (Fig. 21.2). However, the affinity of this enzyme for fructose is much lower than for glucose, making it unlikely that this conversion is on the main pathway of fructose assimilation.

The Liver contains another enzyme, called fructokinase, which catalyzes The transfer of a phosphate group from ATP to fructose, yielding fructose-1-phosphate. Fructokinase is also found in the Kidneys and intestines. This enzyme does not catalyze glucose phosphorylation, and its activity (unlike that of glucokinase) is unaffected by either fasting or Insulin; this explains why fructose is cleared from the Blood at a normal rate in diabetic patients. The $K_m$ value of liver fructokinase for fructose is very low, indicating an extremely high affinity of the enzyme for this substrate. The Formation of fructose-1-phosphate appears to be the primary pathway of fructose phosphorylation. In the absence of liver fructokinase, essential fructosuria is observed.

Fructose-1-phosphate is cleaved into D-glyceraldehyde and dihydroxyacetone phosphate by aldolase B, which is present in The Liver and is also capable of splitting fructose-1,6-bisphosphate. A deficiency of this enzyme causes hereditary fructose intolerance. D-glyceraldehyde can enter Glycolysis after phosphorylation to glyceraldehyde-3-phosphate. This reaction is catalyzed by another liver enzyme, triose kinase. The two triose phosphates—dihydroxyacetone phosphate and glyceraldehyde-3-phosphate—can either be further metabolized via The Glycolytic Pathway or condensed by the action of aldolase, followed by conversion into glucose. Fructose METABOLISM in the liver proceeds primarily via the latter pathway.

In genetically determined fructose intolerance or insufficient activity of fructose-1,6-diphosphatase, fructose-induced hypoglycemia occurs despite large Glycogen reserves. Fructose-1-phosphate and fructose-1,6-bisphosphate likely inhibit liver phosphorylase via an allosteric mechanism.

If the liver and intestines of an experimental animal are removed, intravenously administered fructose is not converted into glucose, and the animal may die of hypoglycemia unless given a glucose injection. Evidence suggests that in humans, fructose can be converted into glucose and lactate in the kidneys. Unlike rats, humans convert a significant amount of the fructose produced from sucrose Digestion into glucose within the intestinal mucosal Cells before it enters the portal Venous system. Fructose metabolism in the liver via the glycolytic pathway proceeds much faster than glucose metabolism. This is because fructose bypasses the step characteristic of glucose metabolism that is catalyzed by Phosphofructokinase—the stage where Metabolic control over The rate of Glucose Catabolism is exerted. Consequently, fructose can intensify metabolic processes in the liver leading to fatty acid synthesis, their Esterification, and the secretion of very-low-density Lipoproteins, which can result in elevated plasma triacylglycerol concentrations.

Free fructose is found in seminal fluid; it is also secreted in large quantities into the Fetal Circulation of ungulates and cetaceans and accumulates in the amniotic and allantoic fluids.

Sorbitol Metabolism

Both fructose and sorbitol have been found in the human lens, with their concentrations increasing in diabetes. They likely play a role in the Pathogenesis of diabetic cataracts. The formation of fructose from glucose (Fig. 21.2) occurs via the "sorbitol pathway" (a polyol pathway absent in the liver), which is activated in diabetic patients when glucose concentrations rise. Glucose is reduced to sorbitol by NADPH in a reaction catalyzed by aldose reductase; sorbitol is then oxidized to fructose in the presence of NAD and sorbitol dehydrogenase (polyol dehydrogenase). Sorbitol penetrates Cell membranes with difficulty and therefore accumulates within The Cell. Aldose reductase is found in the sheep Placenta, where it ensures The production of sorbitol, which is secreted into the fetal blood. The presence of sorbitol dehydrogenase in the liver, including the fetal liver, ensures The conversion of sorbitol into fructose. Intravenously administered sorbitol is indeed converted predominantly into fructose rather than glucose; upon oral administration, its intestinal absorption is negligible, and it is fermented by Large Intestine Bacteria to yield acetate and $ ext{H}_2$.

Sweet products containing sorbitol may cause abdominal pain in individuals with sorbitol intolerance.

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Fig. 21.2. Fructose metabolism. Aldolase A is found in all Tissues except the liver, which contains only aldolase B. Aldose reductase is absent in the liver.