Fructose Metabolism

The predominant site of fructose metabolism is the liver, where fructose enters the intermediary pathways of carbohydrate metabolism. Fructose is readily extracted by the liver because of the presence of an active hepatic enzyme system for metabolizing fructose, and the majority of ingested fructose is cleared in a single pass through the liver. Thus, the concentration of fructose circulating in blood is low after consumption of moderate amounts of fructose. Other tissues that take up small quantities of fructose include the kidney, skeletal muscle, and adipose tissue. The GLUT-5 transporter is expressed in these tissues but at relatively low levels.

In the liver, fructose is phosphorylated and forms fructose-1-phosphate. This reaction requires ATP and is catalyzed by fructokinase (EC 2.7.1.4), an enzyme with high affinity and specificity for fructose. Fructose-1-phosphate is then cleaved by hepatic aldolase (aldolase B; EC 4.1.2.13) to form dihydroxyacetone phosphate (DHAP) and glyceraldehyde. DHAP is an intermediate metabolite in both the gluconeogenic and glycolytic pathways. Thus, a portion of the original fructose carbon structure forms glucose, and, in fact, a small increase in circulating glucose occurs after ingestion of fructose. The glyceraldehyde intermediate is phosphorylated by triokinase (EC 2.7.1.28) to form glyceraldehyde-3-phosphate, another intermediate in the glycolytic pathway. The triose phosphate compounds provide substrate for glycolysis and oxidative metabolism, formation of glycogen, and synthesis of glucose and fatty acids. With the formation of the triose phosphates, the metabolism of fructose and glucose converges. However, prior to this step, there are important differences in fructose and glucose metabolism that impact both carbohydrate and lipid metabolism. The initial reaction that primes fructose for entry to the glycolytic pathway allows it to bypass the critical rate-limiting step of glycolysis. This critical step precedes the formation of triose phosphates; glucose carbons pass through an intermediate step in which fructose-6-phosphate is converted to fructose-1,6-bis-phosphate. This reaction is catalyzed by the allosterically regulated enzyme phosphofructokinase (PFK; EC 2.7.1.11) and is the most important control point in the glycolytic sequence. Among the multiple effectors of PFK are ATP and citrate; these products of glucose oxidation exert an inhibitory effect on the enzyme (Figure 1). The

Fructose

Fructokinase

Fructose 1,6-bisphosphatase

Glucose

| Glucokinase

| Phosphoglucoisomerase Insulin © Fructose 6-P

Phosphofructokinase

0 ATP Citrate

Fructose 1-P

Glyceraldehyde

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