Fructose Metabolism

About 10% of the calories in the Western diet are supplied by fructose (~55 g/day). The major source of fructose is the disaccharide sucrose, which, when cleaved in the intestine, releases equimolar amounts of fructose and glucose.
Fructose is also found as a free monosaccharide in many fruits, in honey, and in high-fructose corn syrup (typically, 55% fructose and 45% glucose), which is used to sweeten soft drinks and many foods . Fructose transport into cells is not insulin dependent (unlike that of glucose into certain tissues), and, in contrast to glucose, fructose does not promote the secretion of insulin.
A. Phosphorylation
For fructose to enter the pathways of intermediary metabolism, it must first be phosphorylated (Fig. 1). This can be accomplished by either hexokinase or fructokinase. Hexokinase phosphorylates glucose in most cells of the body , and several additional hexoses can serve as substrates for this enzyme. However, it has a low affinity (that is, a high Michaelis constant [K_m];) for fructose. Therefore, unless the intracellular concentration of fructose becomes unusually high, the normal presence of saturating concentrations of glucose means that little fructose is phosphorylated by hexokinase. Fructokinase provides the primary mechanism for fructose phosphorylation (see Fig. 1). The enzyme has a low K_m for fructose and a high V_max ([maximal velocity] . It is found in the liver (which processes most of the dietary fructose), kidneys, and the small intestine and converts fructose to fructose 1-phosphate, using ATP as the phosphate donor. 

Figure 1: Fructose phosphorylation products and their cleavage. = phosphate; ADP = adenosine diphosphate.
B. Fructose 1-phosphate cleavage
Fructose 1-phosphate is not phosphorylated to fructose 1,6- bisphosphate as is fructose 6-phosphate  but is cleaved by aldolase B (also called fructose 1-phosphate aldolase) to two trioses, dihydroxyacetone phosphate (DHAP) and glyceraldehyde. [Note: Humans express three aldolase isozymes (the products of three different genes): aldolase A in most tissues; aldolase B in the liver, kidneys, and small intestine; and aldolase C in the brain. All cleave fructose 1,6-bisphosphate produced during glycolysis to DHAP and glyceraldehyde 3-phosphate , but only aldolase B cleaves fructose 1-phosphate.] DHAP can be used in glycolysis or gluconeogenesis, whereas glyceraldehyde can be metabolized by a number of pathways, as illustrated in Figure 2.

Figure 2: Summary of fructose metabolism. P = phosphate; Pi = inorganic phosphate; NAD(H) = nicotinamide adenine dinucleotide; ADP = adenosine diphosphate.
C. Kinetics
The rate of fructose metabolism is more rapid than that of glucose because triose production from fructose 1-phosphate bypasses phosphofructokinase-1, the major rate-limiting step in glycolysis .
D. Disorders
A deficiency of one of the key enzymes required for the entry of fructose into metabolic pathways can result in either a benign condition as a result of fructokinase deficiency (essential fructosuria) or a severe disturbance of liver and kidney metabolism as a result of aldolase B deficiency (hereditary fructose intolerance [HFI]), which occurs in ~1:20,000 live births (see Fig. 2). The first symptoms of HFI appear when a baby is weaned from lactose-containing milk and begins ingesting food containing sucrose or fructose. Fructose 1-phosphate accumulates, resulting in a drop in the level of inorganic phosphate (Pi) and, therefore, of ATP production. As ATP falls, adenosine monophosphate (AMP) rises. The AMP is degraded, causing hyperuricemia (and lactic acidemia). The decreased availability of hepatic ATP decreases gluconeogenesis (causing hypoglycemia with vomiting) and protein synthesis (causing a decrease in blood-clotting factors and other essential proteins). Renal reabsorption of Pi is also decreased. [Note: The drop in Pi also inhibits glycogenolysis .] Diagnosis of HFI can be made on the basis of fructose in the urine, enzyme assay using liver cells, or by DNA-based testing . With HFI, sucrose, as well as fructose, must be removed from the diet to prevent liver failure and possible death. [Note: Individuals with HFI display an aversion to sweets and, consequently, have an absence of dental caries.]
E. Mannose conversion to fructose 6-phosphate
Mannose, the C-2 epimer of glucose , is an important component of glycoproteins . Hexokinase phosphorylates mannose, producing mannose 6-phosphate, which, in turn, is reversibly isomerized to fructose 6-phosphate by phosphomannose isomerase. [Note: Most intracellular mannose is synthesized from fructose or is preexisting mannose produced by the degradation of glycoproteins and salvaged by hexokinase. Dietary carbohydrates contain little mannose.]
F. Glucose conversion to fructose via sorbitol
Most sugars are rapidly phosphorylated following their entry into cells. Therefore, they are trapped within the cells, because organic phosphates cannot freely cross membranes without specific transporters. An alternate mechanism for metabolizing a monosaccharide is to convert it to a polyol (sugar alcohol) by the reduction of an aldehyde group, thereby producing an additional hydroxyl group.
1. Sorbitol synthesis: Aldose reductase reduces glucose, producing sorbitol (or, glucitol; Fig. 3), but the Km is high. This enzyme is found in many tissues, including the retina, lens, kidneys, peripheral nerves, ovaries, and seminal vesicles. A second enzyme, sorbitol dehydrogenase, can oxidize sorbitol to fructose in cells of the liver, ovaries, and seminal vesicles (see Fig. 3). The two-reaction pathway from glucose to fructose in the seminal vesicles benefits sperm cells, which use fructose as a major carbohydrate energy source. The pathway from sorbitol to fructose in the liver provides a mechanism by which any available sorbitol is converted into a substrate that can enter glycolysis.

Figure 3: Sorbitol metabolism. NAD(H) = nicotinamide adenine dinucleotide; NADP(H) = nicotinamide adenine dinucleotide phosphate.
2. Hyperglycemia and sorbitol metabolism: Because insulin is not required for the entry of glucose into cells of the retina, lens, kidneys, and peripheral nerves, large amounts of glucose may enter these cells during times of hyperglycemia (for example, in uncontrolled diabetes). Elevated intracellular glucose concentrations and an adequate supply of reduced nicotinamide adenine dinucleotide phosphate (NADPH) cause aldose reductase to produce a significant increase in the amount of sorbitol, which cannot pass efficiently through cell membranes and, therefore, remains trapped inside the cell (see Fig. 3). This is exacerbated when sorbitol dehydrogenase is low or absent (for example, in cells of the retina, lens, kidneys, and peripheral nerves). As a result, sorbitol accumulates in these cells, causing strong osmotic effects and cell swelling due to water influx and retention. Some of the pathologic alterations associated with diabetes can be partly attributed to this osmotic stress, including cataract formation, peripheral neuropathy, and microvascular problems leading to nephropathy and retinopathy . [Note: Use of NADPH in the aldose reductase reaction decreases the generation of reduced glutathione, an important antioxidant , and may be related to diabetic complications.]