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. 12.4), 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. 12.4). 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.
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. 12.4). 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 (see p. 345). [Note: Use of NADPH in the aldose reductase reaction decreases the generation of reduced glutathione, an important antioxidant (see p. 148), and may be related to diabetic complications.]
III. GALACTOSE METABOLISM
The major dietary source of galactose is lactose (galactosyl β-1,4-glucose) obtained from milk and milk products. [Note: The digestion of lactose by βgalactosidase (lactase) of the intestinal mucosal cell membrane was discussed on p. 87.] Some galactose can also be obtained by lysosomal degradation of glycoproteins and glycolipids. Like fructose (and mannose), the transport of galactose into cells is not insulin dependent.
A. Phosphorylation
Like fructose, galactose must be phosphorylated before it can be further metabolized. Most tissues have a specific enzyme for this purpose, galactokinase, which produces galactose 1-phosphate (Fig. 12.5). As with other kinases, ATP is the phosphate donor.
B. Uridine diphosphate–galactose formation