BIOCHEMISTRY: A TEXTBOOK FOR HIGHER EDUCATION INSTITUTIONS - E. S. Severin - 2004

CHAPTER 7. CARBOHYDRATE METABOLISM

XIII. Fructose and Galactose Metabolism

The METABOLISM of FRUCTOSE AND GALACTOSE includes pathways for their utilization in the Synthesis of Other substances (Heteropolysaccharides, lactose, etc.) and their Participation in the body's energy supply. In the latter case, fructose and galactose are converted in the Liver into either glucose or intermediates of glucose metabolism. Consequently, As a result of these processes, fructose and galactose, along with glucose, can be oxidized to CO₂ and H₂O or utilized for the synthesis of Glycogen and triacylglycerols.

Impaired fructose and Galactose Metabolism can be caused by defects in the Enzymes that catalyze the intermediate reactions of their conversion. Although relatively rare, these disorders can pose a serious threat because the accumulating intermediate metabolites of fructose and galactose are toxic.

A. Fructose Metabolism

A significant amount of fructose produced during The breakdown of sucrose is converted into glucose directly within the intestinal Cells before entering the PORTAL VEIN SYSTEM. Another portion of fructose is absorbed via a carrier protein, i.e., through Facilitated Diffusion.

Fructose metabolism (Fig. 7-69) begins with a phosphorylation reaction (reaction 1) catalyzed by fructokinase, yielding fructose-1-phosphate. This enzyme is found in the liver, as well as in the Kidneys and intestines. Fructokinase exhibits absolute Specificity; therefore, unlike glucokinase, Insulin does not affect its activity. This explains why The rate of fructose excretion in the urine does not differ between patients with Diabetes Mellitus and healthy individuals. Fructose-1-phosphate cannot be converted into fructose-6-phosphate due to the absence of the corresponding enzyme. Instead, fructose-1-phosphate is further cleaved by fructose-1-phosphate aldolase (aldolase B) into glyceraldehyde and dihydroxyacetone-3-phosphate (reaction 2). The latter is an intermediate of Glycolysis and is formed in a reaction catalyzed by fructose-1,6-bisphosphate aldolase (aldolase A). Glyceraldehyde can enter glycolysis after being phosphorylated with the participation of ATP (reaction 3). The two triose phosphate molecules either undergo The Glycolytic Pathway or condense to form fructose-1,6-bisphosphate, subsequently participating in Gluconeogenesis (reactions 8, 7, 5, 9). Fructose in the liver primarily enters the second pathway. A portion of dihydroxyacetone-3-phosphate can be reduced to glycerol-3-phosphate and participate in the synthesis of triacylglycerols.

Class="center">Fig. 7-69. Fructose metabolism. a — conversion of fructose into dihydroxyacetone-3-phosphate and glyceraldehyde-3-phosphate; b — pathway of fructose entry into glycolysis and gluconeogenesis; c — pathway of fructose entry into glycogen synthesis.

It should be noted that The entry of fructose into metabolism via fructose-1-phosphate bypasses the step catalyzed by Phosphofructokinase (reaction 6), which serves as the Metabolic control point for the rate of Glucose Catabolism. This explains why an increased intake of fructose accelerates processes in the liver leading to fatty acid synthesis and their subsequent Esterification to form triacylglycerols.

B. Disorders of fructose metabolism

Disorders of fructose metabolism caused by enzymatic defects are summarized in Table 7-5.

Table 7-5. Disorders of fructose metabolism

Fructokinase deficiency is clinically asymptomatic. Fructose accumulates in the Blood and is excreted in the urine, where it can be detected by laboratory Methods. It is crucial not to confuse this harmless anomaly with diabetes mellitus. This condition is known as benign essential fructosuria and occurs with a frequency of 1:130,000.

Hereditary fructose intolerance, caused by a genetically determined defect in fructose-1-phosphate aldolase, does not manifest as long as the infant is fed breast milk—that is, while the diet is free of fructose. Symptoms appear when fruits, juices, and sucrose are added to the diet. Vomiting, abdominal pain, diarrhea, hypoglycemia, and even coma and seizures occur within 30 minutes after consuming fructose-containing food. Infants and young children who continue to ingest fructose develop chronic liver and kidney dysfunction. Fructose intolerance is a relatively common autosomal recessive form of pathology.

Aldolase fructose-1-phosphate deficiency is accompanied by the accumulation of fructose-1-phosphate, which inhibits The activity of phosphoglucomutase. This enzyme converts glucose-1-phosphate to glucose-6-phosphate and ensures the entry of the Glycogen phosphorylase reaction product into metabolism. Consequently, glycogen breakdown is inhibited at the stage of glucose-1-phosphate formation, leading to hypoglycemia. As a result, lipid mobilization and Fatty acid oxidation are accelerated. Accelerated fatty acid oxidation and the synthesis of Ketone Bodies, which substitute for the energetic function of glucose, can lead to metabolic acidosis (see Chapter 8) because ketone bodies are acids and, at high concentrations, lower blood pH.

The inhibition of Glycogenolysis and glycolysis results in decreased ATP synthesis. In addition, the accumulation of phosphorylated fructose disrupts inorganic phosphate metabolism and causes hypophosphatemia.

To replenish intracellular phosphate, the degradation of adenylyl NUCLEOTIDES is accelerated. The breakdown products of these nucleotides enter catabolism, passing through stages of hypoxanthine, xanthine, and ultimately uric acid formation. An elevated level of uric acid coupled with impaired urate excretion under conditions of metabolic acidosis manifests as hyperuricemia. Hyperuricemia can lead to Gout even at a young age (see Chapter 10).

C. Galactose metabolism

Galactose is produced in the intestine via the Hydrolysis of lactose. To convert galactose into glucose, it is necessary to alter the optical configuration of the H and OH groups at the C₄ atom of galactose, i.e., to carry out an epimerization reaction. In The Cell, this reaction is possible only with the UDP-derivative of galactose. UDP-galactose is formed from UDP-glucose (an intermediate in glycogen synthesis) in a reaction catalyzed by uridylphosphate-4-epimerase (Figs. 7-70, 7-71).

Fig. 7-70. Galactose metabolism.

Fig. 7-71. Epimerization of UDP-glucose to UDP-galactose.

However, the incorporation of galactose into the aforementioned epimerization pathway is preceded by its phosphorylation to form galactose-1-phosphate (Reaction 1 in Fig. 7-70). Subsequently, galactose-1-phosphate displaces the glucose residue in UDP-glucose to yield UDP-galactose (Reaction 2); in other words, a direct reaction between phosphorylated galactose and UTP does not occur.

Reaction 2 can be viewed as The transfer of the uridylyl moiety from UDP-glucose to galactose, which is why the enzyme is designated as galactose-1-phosphate uridylyltransferase (GALT).

Next, the galactose bound to the nucleotide enters the epimerization reaction, which involves an epimerase—a NAD-dependent enzyme that catalyzes the Oxidation and reduction of galactose at the C₄ carbon atom (Reaction 3).

The epimerase can also operate in reverse, converting UDP-glucose into UDP-galactose. This reverse epimerization is crucial for the synthesis of galactosyl residues in Glycolipids and Glycoproteins. Furthermore, galactose is essential for lactose synthesis in the Mammary Glands. During Lactation, dietary galactose is not an essential nutrient because it can be synthesized from glucose.

Glucose-1-phosphate produced in Reaction 2 can enter Various metabolic pathways: 1) glycogen synthesis following reaction with UDP to form UDP-glucose; 2) conversion in the liver into free glucose to maintain blood glucose levels; 3) catabolism coupled with ATP synthesis, etc. (see Fig. 7-70).

G. Disorders of Galactose Metabolism

Galactose metabolism is of particular interest due to its association with a hereditary disorder known as galactosemia.

Galactosemia arises from impaired galactose metabolism caused by an inherited defect in any of the three enzymes responsible for channeling galactose into glucose metabolism (Table 7-6).

Table 7-6. Disorders of Galactose Metabolism

Galactosemia caused by galactose-1-phosphate uridylyltransferase (GALT) deficiency is the most thoroughly studied. This condition manifests very early and poses a severe threat to infants, as their primary source of CARBOHYDRATES is breast milk, which contains lactose. Early symptoms of GALT deficiency include vomiting, diarrhea, dehydration, weight loss, and jaundice. They appear shortly after birth as soon as the infant begins feeding on milk. The concentrations of galactose and galactose-1-phosphate are elevated in the blood, urine, and Tissues. Within eye tissues (specifically the lens), galactose is reduced by aldose reductase to form galactitol (dulcitol), with NADPH serving as the hydrogen donor in this reaction. Although galactose reduction also occurs during normal metabolism, it proceeds at a very low rate. In galactosemia, galactitol accumulates in the vitreous body and binds large amounts of Water. As a result, electrolyte balance is disrupted, and excessive Hydration of the lens leads to The Development of cataracts, which become apparent within just a few days of life.

Severe consequences of GALT deficiency are observed in the liver, driven by the accumulation of galactose-1-phosphate and its cytotoxic effects on hepatocytes. This leads to impaired liver function, including hepatomegaly and Fatty liver degeneration. The concentrations of galactitol and galactose-1-phosphate are also elevated in the kidneys of such patients, compromising renal function. Damage to cells in the cerebral hemispheres and Cerebellum has been noted, and in severe cases, cerebral edema, mental retardation, and even death may occur.

Galactosemia caused by galactokinase deficiency is likewise characterized by cataracts; however, unlike GALT deficiency, it does not involve dysfunctions of the liver, kidneys, or Brain. The most severe consequences of reduced GALT activity are attributed to the inhibitory effect of galactose-1-phosphate on Other Enzymes involved in carbohydrate

metabolism (phosphoglucomutase, glucose-6-phosphate dehydrogenase).

Several forms of galactosemia resulting from GALT deficiency are known (Table 7-7).

Table 7-7. Selected Variants of Genetic GALT Defects

Certain structural defects in GALT lead only to a partial loss of enzymatic activity. Since GALT is normally present in the body in excess, a reduction in its activity to 50% or even lower may remain clinically silent.

The Diagnosis of galactosemia involves testing urine for galactose content following several milk feedings. If a cataract is detected in an infant, screening for galactokinase and GALT deficiencies is performed. The presence of galactose in the urine in the absence of liver dysfunction points to a galactokinase defect. A galactose tolerance test is strongly discouraged during evaluation, as it poses significant risks to affected patients. Management consists of the complete elimination of galactose from the diet.