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9.1: Monosaccharide metabolism

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    Fructose metabolism

    Fructose is a dietary component of sucrose in fruit, as a free sugar in honey, and in high-fructose corn syrup. It is taken up by cells through facilitated diffusion through the GLUT5 transporter. Fructose is metabolized principally in the liver, and the initial step involves phosphorylation at the 1-position to form fructose 1-phosphate (figure 9.1). Fructokinase, the major kinase involved, phosphorylates fructose in the 1-position. Fructokinase has a high \(V_{max}\) and rapidly phosphorylates fructose as it enters the cell. Aldolase B cleaves fructose 1-phosphate into glyceraldehyde 3-phosphate and dihydroxyacetone-phosphate, which can enter directly into glycolysis.

    Fructose arrow enzyme fructokinase with ATP arrow ADP to fructose 1-P arrow enzyme aldolase B with loss of dihydroxyacetone-P to glyceraldehyde arrow enzyme triose kinase with ATP arrow ADP to glyceraldehyde 3-P dotted arrow pyruvate arrow TCA cycle with loss of fatty acids to TCA cycle. Pyruvate bidirectional arrow lactate. Glucose arrow enzyme hexokinase with ATP arrow ADP to glucose 6-P bidirectional arrow fructose 6-P circular bidirectional arrows fructose 1,6-BP bidirectional arrows with aldolase B (liver) and aldolase A (muscle) to glyceraldehyde 3-P and dihydroxyacetone-P. Glucose 6-P bidirectional arrow Glucose 1-P circular bidirectional arrows glycogen.

    Figure 9.1: Convergence of fructose and glucose metabolism.

    Aldolase B is the rate-limiting enzyme of fructose metabolism, although it is not a rate-limiting enzyme of glycolysis. Aldolase B's affinity for fructose 1-phosphate is lower than fructose 1,6-bisphosphate and is very slow at physiological levels of fructose 1-phosphate. Consequently, after high fructose consumption, fructose 1-phosphate will accumulate in the liver, and it is slowly converted to glycolytic intermediates over time (figures 9.1 and 9.2).

    Deficiencies in fructose metabolism

    Essential fructosuria (fructokinase deficiency) and hereditary fructose intolerance (HFI) (a deficiency of the fructose 1-phosphate cleavage by aldolase B) are inherited disorders of fructose metabolism. A deficiency in fructokinase is a benign genetic disorder. In this case, an individual will have fructosuria; fructose is not phosphorylated and trapped in the cell. Consequently, any ingested fructose is shed in the urine. Hereditary fructose intolerance is caused by a deficiency in aldolase B and results in an accumulation of fructose 1-phosphate in the hepatocytes. Inability to metabolize fructose 1-phosphate can cause significant clinical symptoms, most notably hepatomegaly and fasting hypoglyemia. The accumulation of fructose 1-phosphate eventually inhibits both glycogenolysis and gluconeogenesis (due to a lack of free phosphate), leading to bouts of fasting hypoglycemia.

    Galactose metabolism

    Galactose is consumed principally as lactose, which is cleaved to galactose and glucose in the intestine. Galactose is subsequently phosphorylated to galactose 1-phosphate by galactokinase (primarily in the liver). Following phosphorylation, galactose 1-phosphate is activated to a uridine diphosphate (UDP)-sugar by galactosyl uridylyltransferase (GALT). The metabolic pathway subsequently generates glucose 1-phosphate, which enters into the glycolytic pathway (figure 9.2)

    Fructose arrow with ATP arrow ADP and enzyme fructokinase to Fructose 1-phosphate bidirectional branched arrows enzyme fructose 1-P aldolase (aldolase B) to dihydroxyacetone phosphate (DHAP) and glyceraldehyde. DHAP bidirectional arrow enzyme triosephosphate isomerase to glyceraldehyde 3-phosphate. Glyceraldehyde arrow with ATP arrow ADP and enzyme triose kinase to glyceraldehyde 3-phosphate.

    Figure 9.2: Fructose metabolism and reaction by aldolase B. Deficiencies in aldolase B can result in hereditary fructose intolerance, while deficiencies in frutokinase can result in essential fructosuria.

    Deficiencies in galactose metabolism

    Classical galactosemia, a deficiency of galactosyl uridylyltransferase (GALT), results in the accumulation of galactose 1-phosphate in the liver and the inhibition of hepatic glycogen metabolism and other pathways that require UDP-sugars. Cataracts can occur from the accumulation of galactose in the blood, which is converted to galactitol (the sugar alcohol of galactose) in the lens of the eye.

    Galactitol bidirectional arrow enzyme aldose reductase with NADP+ bidirectional arrow NADPH to galactose arrow enzyme galactokinase with ATP arrow ADP to galactose 1-phosphate arrow UDP-galactose arrow enzyme galactose 1-phosphate uridyltransferase (GALT) to Glucose 1-phosphate arrow enzyme UTP glucose 1-phosphate uridyltransferase to UDP-glucose arrow enzyme UDP-glucose dehydrogenase with 2 NAD+ arrow 2 NADH and loss of glycosaminoglycans (GAGs), glycoproteins, and glycolipids to UDP-glucuronate. UDP-galactose arrow enzyme UDP-galactose epimerase to UDP-glucose arrow UDP-galactose. UDP-galactose arrow enzyme lactose synthase (inside Golgi) with Glucose arrow UDP to lactose. UDP-glucose arrow UDP arrow with ATP arrow ADP to UTP arrow touching between glucose 1-phosphate and UDP-glucose to PPi arrow with H2O addition to 2 Pi.

    Figure 9.3: Galactose metabolism; glucose 6-phosphate is converted to glucose 1-phosphate, which enters the pathway.

    The accumulating galactose 1-phosphate is especially toxic for the liver, kidneys, and central nervous system. If left untreated, the disease is fatal due to complications such as gram-negative sepsis or hepatic and renal failure. The absence of GALT activity can be detected any time after birth and screened for as part of newborn screening. It is essential to obtain results promptly, because children with classic galactosemia can have a life-threatening crisis within the first few days after birth. Infants with a positive result are placed on a lactose-free formula, and confirmatory testing is accomplished by measuring specific metabolite concentrations and enzyme activity in erythrocytes.

    Nonclassical galactosemia causes fewer medical complications and presents with a different pattern of symptoms. Presentations can involve cataracts, delayed development, and kidney problems.

    Galactose arrow labeled nonclassical galactosemia with ATP arrow ADP and enzyme galactokinase to galactose-1-phosphate arrow labeled classical galactosemia and enzyme galactose 1-phosphate uridylyltransferase to glucose-1-phosphate arrow glucose-6-phosphate arrow text liver glucose. At classical galactosemia arrow, UDP glucose arrow UDP galactose arrow enzyme epimerase arrow UDP-glucose. Glucose-6-phosphate arrow glycolysis (other tissues).

    Figure 9.4: Comparison of classical and nonclassical galatosemia.

    References and resources

    Text

    Ferrier, D. R., ed. Lippincott Illustrated Reviews: Biochemistry, 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2017, Chapter 12: Metabolism of Monosaccharides and Disaccharides, Chapter 23: Effects of Insulin and Glucagon: Section IV.

    Le, T., and V.  Bhushan. First Aid for the USMLE Step 1, 29th ed. New York: McGraw Hill Education, 2018, 72, 80–81.

    Lieberman, M., and A. Peet, eds. Marks' Basic Medical Biochemistry: A Clinical Approach, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2018, Chapter 22: Generation of ATP from Glucose, Fructose and Galactose, Chapter 33: Ethanol Metabolism.

    Figures

    Grey, Kindred, Figure 9.1 Convergence of fructose and glucose metabolism. 2021. https://archive.org/details/9.1_20210926. CC BY 4.0.

    Grey, Kindred, Figure 9.2 Fructose metabolism and reaction by Aldolase B. Deficiencies in aldolase B can result in hereditary fructose intolerance while deficiencies in frutokinase can result in essential fructosuria. 2021. https://archive.org/details/9.2_20210926. CC BY 4.0.

    Grey, Kindred, Figure 9.3 Galactose metabolism; glucose 6-phosphate is converted to glucose 1-phosphate which enters the pathway. 2021. https://archive.org/details/9.3_20210926. CC BY 4.0.

    Grey, Kindred, Figure 9.4 Comparison of Classical and Nonclassical galatosemia. 2021. https://archive.org/details/9.4_20210926. CC BY 4.0.

    This page titled 9.1: Monosaccharide metabolism is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Renee J. LeClair (Virginia Tech Libraries' Open Education Initiative) .