Principles of Biochemistry Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Glycolysis: The Central Pathway of Glucose Catabolism
Other simple sugars can also enter the glycolytic pathway

In animal Tissues, Glycolysis degrades not only glucose but also other Monosaccharides which, following appropriate conversions, can likewise be broken down to release their stored energy (Fig. 15-8).

D-Fructose, which occurs in free form in many fruits and is formed in the Small Intestine from sucrose (also known as cane or beet sugar), can be phosphorylated in the presence of hexokinase, an enzyme acting on A wide variety of hexoses:

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This is the primary pathway for The entry of fructose into glycolysis in Muscle and Kidney tissues.

Fig. 15-11. a-D-Fructose-1-phosphate as an intermediate in The conversion of fructose to glyceraldehyde phosphate.

In the Liver, however, a different pathway exists. Fructokinase, present in this tissue, catalyzes the phosphorylation of fructose not at carbon atom 6, but at carbon atom 1 (Fig. 15-11):

Fructose-1-phosphate is then cleaved by the action of aldolase to yield D-glyceraldehyde and dihydroxyacetone phosphate:

Dihydroxyacetone phosphate is, as is well known, one of the intermediates of glycolysis, readily converted into glyceraldehyde-3-phosphate. The other product of the above reaction, D-glyceraldehyde, is phosphorylated by ATP in a reaction catalyzed by the enzyme triokinase, which also leads to glyceraldehyde-3-phosphate:

Thus, two molecules of glyceraldehyde-3-phosphate are generated from a single molecule of D-fructose in the liver.

D-Galactose, produced by the Hydrolysis of the disaccharide lactose (milk sugar), is first phosphorylated at carbon atom 1 by ATP in a reaction catalyzed by galactokinase:

The product of this reaction, D-galactose-1-phosphate, is converted into its C₄-epimer, namely D-glucose-1-phosphate. This conversion proceeds in several steps (Fig. 15-12). These reactions involve uridine diphosphate (UDP), which acts as a coenzyme-like carrier of hexose groups. In the human liver, galactose-1-phosphate reacts with UDP-glucose to yield UDP-D-galactose and glucose-1-phosphate. This reaction is catalyzed by the enzyme UDP-glucose: a-D-galactose-1-phosphate uridylyltransferase. The galactose moiety of UDP-D-galactose then undergoes epimerization at carbon atom 4, catalyzed by the enzyme UDP-glucose epimerase (Fig. 15-12), to form UDP-D-glucose. UDP-glucose pyrophosphorylase catalyzes the Cleavage of UDP-glucose to produce D-glucose-1-phosphate, which is converted to glucose-6-phosphate by phosphoglucomutase. This sequence of reactions is responsible not only for the conversion of D-galactose into D-glucose, but also for the reverse process—the synthesis of D-galactose in the Mammary Glands (where D-galactose is required for The production of lactose, or milk sugar). The vital role of UDP as a glycosyl group carrier was discovered through the pioneering work of the Argentine biochemist Luis Leloir. Later, we will examine other metabolic pathways where UDP-sugar derivatives serve as intermediates.

In one of the most common forms of this congenital metabolic disorder,

Fig. 15-12. A. Pathway for the conversion of D-galactose to D-glucose. B. Detailed view of the UDP-glucose 4-epimerase reaction (highlighted by a box in panel A).

The NAD required by The enzyme catalyzing the interconversion of UDP-glucose and UDP-galactose presumably accepts two hydrogen atoms from the fourth carbon atom of the glucose moiety and subsequently returns them to yield the C₄ epimer.

Deficiency of the enzyme UDP-glucose: a-D-galactose-1-phosphate uridylyltransferase causes galactosemia, a hereditary human disease that manifests in early infancy. Because the conversion of galactose to glucose is impaired, galactose and galactose-1-phosphate—derived from the Digestion of lactose—accumulate in tissues, causing damage to the Brain and liver, as well as clouding of the lens (cataracts). Significant amounts of free galactose are also detected in the Blood. One of the milder forms of galactosemia is caused by galactokinase deficiency.

such as galactosemia, The Human Body lacks the enzyme UDP-glucose: a-D-galactose-1-phosphate uridylyltransferase due to a genetic defect. Consequently, the conversion of D-galactose into D-glucose becomes impossible. Due to the impaired ability to metabolize D-galactose and D-galactose-1-phosphate, these compounds accumulate in the blood and tissues. This leads to hepatomegaly and enlargement of other Organs, visual impairment from lens opacity (cataracts), and delayed mental development. Since milk lactose is the primary dietary source of D-galactose, this inherited metabolic disorder becomes apparent in infancy. The symptoms of galactosemia can be substantially mitigated by eliminating milk and dairy products from the diet. Other forms of galactosemia arise from genetic abnormalities resulting in a deficiency of galactokinase or UDP-glucose 4-epimerase.

D-Mannose, which is produced during the digestion of various dietary Polysaccharides and Glycoproteins, is phosphorylated at the C-6 position by hexokinase:

Phosphomannose isomerase then catalyzes the isomerization of D-mannose-6-phosphate to D-fructose-6-phosphate, which is one of the intermediates of glycolysis:

Figure 15-8 illustrates all these pathways through which various sugars are channeled into the central glycolytic pathway.