Fructose 1-phosphate is not phosphorylated to fructose 1,6-bisphosphate as is fructose 6-phosphate (see p. 99) 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 (see p. 101), 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 12.3.
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 (see p. 99).
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. 12.3). 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; see p. 299). 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 (see p. 128).] Diagnosis of HFI can be made on the basis of fructose in the urine, enzyme assay using liver cells, or by DNA-based testing (see Chapter 34). 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 (see p. 84), is an important component of glycoproteins (see p. 166). 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