Fructose 1-phosphate is cleaved by aldolase B (also known as fructose 1-phosphate aldolase) into two trioses, dihydroxyacetone phosphate (DHAP) and glyceraldehyde. Humans have three aldolase isozymes: aldolase A in most tissues, aldolase B in the liver, kidneys, and small intestine, and aldolase C in the brain. While all three isozymes cleave fructose 1,6-bisphosphate into DHAP and glyceraldehyde 3-phosphate, only aldolase B cleaves fructose 1-phosphate. DHAP can be used in glycolysis or gluconeogenesis, while glyceraldehyde can be metabolized in various pathways.

The rate of fructose metabolism is faster than that of glucose because triose production from fructose 1-phosphate bypasses the major rate-limiting step in glycolysis, phosphofructokinase-1.

Deficiency of key enzymes required for fructose metabolism can lead to two conditions. Fructokinase deficiency results in a benign condition known as essential fructosuria. On the other hand, aldolase B deficiency causes hereditary fructose intolerance (HFI), a severe disturbance of liver and kidney metabolism. HFI occurs in approximately 1 in 20,000 live births. Symptoms of HFI manifest when a baby is weaned from lactose-containing milk and consumes food with sucrose or fructose. This leads to the accumulation of fructose 1-phosphate, a drop in inorganic phosphate (Pi) levels, and a subsequent decrease in ATP production. As ATP decreases, adenosine monophosphate (AMP) increases. AMP degradation causes hyperuricemia and lactic acidemia. The decrease in hepatic ATP impairs gluconeogenesis and protein synthesis, leading to hypoglycemia with vomiting and a decrease in essential proteins, including blood-clotting factors. Pi reabsorption in the kidneys is also reduced. Diagnosis of HFI can be done through urine fructose measurement, liver cell enzyme assay, or DNA-based testing. Individuals with HFI must eliminate both sucrose and fructose from their diet to prevent liver failure and potential death. Interestingly, individuals with HFI typically display an aversion to sweets and have a lower risk of dental caries.

Mannose, an epimer of glucose at the C-2 position, is an important component of glycoproteins. Hexokinase phosphorylates mannose to produce mannose 6-phosphate, which is then isomerized to fructose 6-phosphate by phosphomannose isomerase. Most intracellular mannose is synthesized from fructose or is derived from the degradation of glycoproteins and salvaged by hexokinase. Dietary carbohydrates contain minimal amounts of mannose.

Glucose can be converted to fructose via sorbitol.
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