Fructolysis

Fructolysis, or fructose metabolism, is the biochemical pathway by which fructose is converted into glycolytic intermediates for energy production and biosynthesis. In humans, the liver is the primary site, with smaller contributions from the intestine and kidney. Fructose enters hepatocytes via transporters such as GLUT2 and GLUT5 and is rapidly processed to bypass several regulatory steps of glycolysis.

The first step is phosphorylation of fructose by fructokinase (ketohexokinase) to fructose-1-phosphate, consuming one molecule of ATP. Fructose-1-phosphate is then cleaved by aldolase B into dihydroxyacetone phosphate (DHAP) and glyceraldehyde. Glyceraldehyde is subsequently phosphorylated by glyceraldehyde kinase (also called triose kinase) to glyceraldehyde-3-phosphate (G3P). DHAP and G3P are glycolytic intermediates that enter downstream pathways to generate ATP or to support gluconeogenesis and biosynthesis.

Fructolysis operates relatively rapidly and can be insulin-independent, which has several metabolic implications. Excessive fructose intake can lead to depletion of cellular ATP and increased production of uric acid via the AMP deaminase pathway. Because fructose metabolism bypasses the major regulatory step of glycolysis, its intake can promote lipogenesis and contribute to metabolic disturbances when consumed in high amounts.

Clinical relevance includes two inherited conditions. Essential fructosuria results from fructokinase deficiency and is typically benign, with fructose appearing in the urine but few symptoms. Hereditary fructose intolerance arises from aldolase B deficiency, causing accumulation of fructose-1-phosphate, phosphate depletion, and impaired glycogenolysis and gluconeogenesis after fructose exposure, leading to hypoglycemia, vomiting, and liver enlargement; management centers on restricting dietary fructose and sucrose.