Fructose Metabolism

 

The major source of fructose is the disaccharide sucrose, which when cleaved in intestine, releases equimolar amounts of fructose and glucose. Fructose is also found as a free monosaccharide in high fructose corn syrup (55% fructose/ 45% glucose, which is used to sweeten most cola drinks), in many fruits and in honey.

Entry of fructose into cells is not insulin dependent (unlike that of glucose into certain tissues), and in contrast to glucose, fructose does not promote secretion of insulin. For fructose to enter pathways of intermediary metabolism. It must first be phosphorylated. This can be accomplished by either hexokinase or fructokinase. Hexokinase phosphorylates glucose in all cells of the body and several additional hexoses can serve as substrate for this enzyme. However, it has a low affinity (high Km) for fructose. Therefore, unless intracellular concentration of fructose becomes unusually high, the normal presence of saturating concentrations of the glucose means that little fructose is converted to fructose -6phosphate by hexokinase. Fructokinase provides the primary mechanism for fructose phosphorylation. It is found in the liver (which processes most of dietary fructose), kidney and small intestinal mucosa and converts fructose to fructose 1 phosphate, using ATP as the phosphate donor. Also, these 3 tissues contain aldolase. Fructose 1-phosphate is not converted to fructose 1,6 bisphosphate as fructose – 6- phosphate, but is converted by aldolase B to dihydroxyacetone phosphate and glyceraldehyde. Both aldolase A (found in all tissues) and aldolase B cleave fructose 1,6 bisphosphate produced during glycolysis to dihydroxyacetone phosphate and glyceraldehyde. dihydroxyacetone phosphate can directly enter glycolysis or gluconeogenesis, whereas glyceraldehyde can be metabolized by a number of pathways.

The rate of fructose metabolism is more rapid than that of glucose because the trioses formed from fructose -1 – phosphate bypass phosphofructokinase, the major rate limiting step in glycolysis.

A deficiency of one of the key enzyme required for the entry of fructose into intermediary metabolic pathways can result in either a benign condition (fructokinase deficiency – essential fructosuria), or a severe disturbance of liver and kidney metabolism as a result of aldolase B deficiency ( hereditary fructose intolerance, HFI – “fructose poisoning”) which is estimated to occur in 1:20,000 live births. The first symptoms appear when a baby is weaned and begins to be fed food containing sucrose or fructose. Fructose -1- phosphate accumulates, and ATP and Pi levels fall significantly, with adenine being converted to uric acid, causing hyperuricemia.

The decreased availability of hepatic ATP affects gluconeogenesis (causing hypoglycemia with vomiting) and protein synthesis ( causing a decrease in blood clotting factor and other essential proteins). If fructose ( and therefore, sucrose) is not removed from diet, liver failure and death can occur. Diagnosis of HFI can be made on basis of fructose in urine, or by a restriction fragment length polymorphism (RFLP) test.

Mannose, the carbon 2 epimer of glucose, is an important component of glycoproteins. Hexokinase phosphorylates mannose, mannose -6- phosphate, which in turn ( reversibly) isomerized to fructose – 6- phosphate by phosphomannose isomerase.

Most sugars are rapidly phosphorylated following their entry into cells. They are thereby trapped within cells, because organic phosphates can’t freely cross membranes without specific transporters. An alternate mechanism for metabolizing a monosaccharides is to convert it to a polyol by reduction of an aldehyde group, thereby producing an additional hydroxyl group.

Aldose reductase reduces glucose, producing sorbitol ( glucitol). This enzyme is found in many tissues, including the lens, retina, Schwann cells of peripheral nerves, liver, kidney, placenta, RBC and cells of the ovaries and seminal vesicles. In cells of liver, ovaries, sperm and seminal vesicles, there is a 2^nd enzyme, sorbitol dehydrogenase, that can oxidize sorbitol to produce fructose. The 2 reaction pathway from glucose to fructose in seminal vesicles is for the benefit of sperm cells, which use fructose as a major CHO energy source. The pathway from sorbitol to fructose in liver provides a mechanism by which any available sorbitol is converted into a substrate that can enter glycolysis or gluconeogenesis.