Metabolism of monosaccharides and disaccharides

Galactose and fructose metabolism as part of the essential pathways of energy metabolism.

Overview Although many monosaccharides have been identified in nature, only a few sugars appear as metabolic intermediates or as structural components in mammals. Gluc is the most common monosacch consumed by humans, & its metabolism has been discussed However, two other monosacch’s, fructose & galactose, occur in significant amounts in the diet, & make important contributions to energy metabolism In addition, galactose is an important component of cell structural CHO’s

Fructose ~ 10% of the calories contained in Western diet are supplied by fructose (~ 50g/day). The major source of fructose is the disaccharide sucrose, which, when cleaved in intestine, releases equimolar amounts of fructose & glucose Fructose is also found as a free monosacch in high-fructose corn syrup (55% fructose/45% glucose, which is used to sweeten most cola drinks), in many fruits, & in honey. Entry of fructose into cells is not insulin-dependent (unlike that of glucose into certain tissues), & in contrast to glucose, fructose does not promote secretion of insulin

Galactose Galactose and glucose are the two monosaccharide sugar components that make up the disaccharide sugar, lactose. Lactose is found primarily in milk and milk products. Galactose metabolism, which converts galactose into glucose, is carried out by the three principal enzymes in a mechanism known as the Leloir Pathway. The enzymes are listed in the order of the metabolic pathway: galactokinase (GALK), galactose-1-phosphate uridyltransferase (GALT), and UDP-galactose-4’-epimerase (GALE).

Once in the bloodstream... Liver Muscle Adipose Galactose Glucose Fructose Conversion to glucose

Hexokinase phosphorylates gluc in all cells of the body, & several additional hexoses can serve as substrates for this enz. it has a low affinity (high Km) for fructose. fructose is converted to F-6-P by hexokinase Fructokinase provides the primary mechanism for fructose phospho. It is found in the liver, kidney, & small intestinal mucosa.

F 1-P is not converted to F 1,6-BP as F-6-P, but is cleaved by aldolase B to DHAP & glyceraldehyde Note: both aldolase A (found in all tissues) & aldolase B cleave F 1,6-BP produced during glycolysis to DHAP & GA-3P. - DHAP can directly enter glycolysis or gluconeogenesis, whereas glyceraldehyde can be metabolized by a number of pathways

Kinetics of fructose metabolism The rate of fructose metabolism is more rapid than that of gluc because the trioses formed from F-1-P bypass PFK, the major rate-limiting step in glycolysis Note: loading the liver with fructose, e.g., by intravenous infusion, can significantly elevate the rate of lipogenesis caused by enhanced production of acetyl CoA

Disorders of fructose metabolism A deficiency of one of the key enz’s required for the entry of fructose into intermediary metabolic pathways can result in either a benign condition (fructokinase deficiency  essential fructosuria), or a severe disturbance of liver & kidney metabolism as a result of aldolase B deficiency (hereditary fructose intolerance, HFI-”fructose poisoning”) which is estimated to occur in 1:20,000 live births The 1st symptoms appear when a baby is weaned & begins to be fed food containing sucrose or fructose. F-1-P accumulates, & ATP & Pi levels fall significantly, with adenine being converted to uric acid, causing hyperuricemia Pi levels fall because Pi is trapped in F-1-P

A deficiency of one of the key enz’s required for the entry of fructose into intermediary metabolic pathways can result in either a benign condition (fructokinase deficiency  essential fructosuria),

(hereditary fructose intolerance, HFI-”fructose poisoning”) which is estimated to occur in 1:20,000 live births The 1st symptoms appear when a baby is weaned & begins to be fed food containing sucrose or fructose. F-1-P accumulates, & ATP & Pi levels fall significantly.

hereditary fructose intolerance The decreased availability of hepatic ATP affects gluconeogenesis (causing hypoglycemia with vomiting), & protein synthesis (causing a decrease in blood clotting factors & other essential proteins) If fructose (& therefore, sucrose) is not removed from diet, liver failure & death can occur Diagnosis of HFI can be made on basis of fructose in urine.

Figure 12.3. Summary of fructose metabolism.

Conversion of mannose to fructose 6-phosphate Mannose, the C-2 epimer of gluc, is an important component of glycoproteins Hexokinase phosphorylates mannose  mannose 6-P, which in turn, is (reversibly) isomerized to F-6-P by phosphomannose isomerase Note: there is little mannose in dietary CHOs. Most intracellular mannose is synthesized from fructose, or is pre-existing mannose produced by degradation of structural CHO’s & salvaged by hexokinase

Conversion of glucose to fructose via sorbitol Most sugars are rapidly phosphorylated following their entry into cells. They are thereby trapped within cells, because organic P’s can’t freely cross memb’s without specific transporters An alternate mechanism for metabolizing a monosacch is to convert it to a polyol by reduction of an aldehyde group, thereby producing an additional hydoxyl group

Synthesis of sorbitol: Aldose reductase reduces glucose, producing sorbitol (glucitol). This enz is found in many tissues, including the lens, retina, Schwann cells of peripheral nerves, liver, kidney, placenta, RBCs, & cells of the ovaries & seminal vesicles. In cells of liver, ovaries, sperm & seminal vesicles, there is a 2nd enz, sorbitol dehydrogenase, that can oxidize sorbitol to produce fructose. The 2-reaction pathway from gluc to fruc in seminal vesicles is for the benefit of sperm cells, which use fruc as a major CHO energy source. The pathway from sorbitol to fruc in liver provides a mechanism by which any available sorbitol is converted into a substrate that can enter glycolysis or gluconeogenesis

Aldose reductase reduces glucose, producing sorbitol (glucitol) Aldose reductase reduces glucose, producing sorbitol (glucitol). This enz is found in many tissues, including the lens, retina, Schwann cells of peripheral nerves, liver, kidney, placenta, RBCs, & cells of the ovaries & seminal vesicles. Sorbitol metabolism

In cells of liver, ovaries, sperm & seminal vesicles, there is a 2nd enz, sorbitol dehydrogenase, that can oxidize sorbitol to produce fructose. The 2-reaction pathway from gluc to fruc in seminal vesicles is for the benefit of sperm cells, which use fruc as a major CHO energy source. The pathway from sorbitol to fruc in liver provides a mechanism by which any available sorbitol is converted into a substrate that can enter glycolysis or gluconeogenesis Sorbitol metabolism

The effect of hyperglycemia on sorbitol metabolism Because insulin is not required for entry of gluc into cells listed in previous paragraph, large amounts of gluc may enter these cells during times of hyperglycemia, e.g., in uncontrolled diabetes. Elevated intracellular gluc conc’s & an adequate supply of NADPH cause aldose reductase to produce a sufficient increase in the amount of sorbitol, which can’t pass efficiently through CMs &, therefore, remains trapped inside cell. This is exacerbated when sorbitol dehydrogenase is low or absent, e.g., in retina, lens, kidney & nerve cells. As a result, sorbitol accumulates in these cells, causing strong osmotic effects &, therefore, cell swelling as a result of water retention Some of the pathologic alterations associated with diabetes can be attributed, in part, to this phenomenon, including cataract formation, peripheral neuropathy, & vascular problems leading to nephropathy, & retinopathy including the lens, retina, Schwann cells of peripheral nerves, liver, kidney, placenta, RBCs, & cells of the ovaries & seminal vesicles.

Elevated intracellular gluc conc’s & an adequate supply of NADPH cause aldose reductase to produce a sufficient increase in the amount of sorbitol, which can’t pass efficiently through CMs &, therefore, remains trapped inside cell. This is exacerbated when sorbitol dehydrogenase is low or absent, e.g., in retina, lens, kidney & nerve cells. As a result, sorbitol accumulates in these cells, causing strong osmotic effects &, therefore, cell swelling as a result of water retention

Galactose metabolism The major dietary source of galactose is lactose (galactosyl β 1,4-glucose) obtained from milk & milk products. Some galactose can also be obtained by lysosomal degradation of complex CHOs, such as glycoproteins & glycolipids, which are important memb components. Like fructose, entry of galactose into cells is not insulin dependent

Phosphorylation of galactose - Like fruc, galactose must be phosphorylated before it can be further metabolized. Most tissues have a specific enz for this purpose, galactokinase, which produces galactose 1-P. ATP is the P donor.

Galactose 1-P can’t enter glycolytic pathway unless it is 1st converted to UDP-galactose. This occurs as an exchange reaction, in which UMP is removed from UDP-gluc (leaving behind G-1-P), & is then transferred to the galactose 1-P, producing UDP-galactose. The enz which catalyzes this reaction is galactose 1-phosphate uridyl transferase

In order for UDP-galactose to enter the mainstream of gluc metabolism, it must 1st be converted to its C-4 epimer, UDP-gluc, by UDP-hexose 4-epimerase

In order for UDP-galactose to enter the mainstream of gluc metabolism, it must 1st be converted to its C-4 epimer, UDP-gluc, by UDP-hexose 4-epimerase

This “new” UDP-gluc (produced from the original UDP-galactose) can then participate in many biosynthetic reactions, as well as being used in uridyl transferase reaction described above, converting another galactose 1-P into UDP-galactose, & releasing G-1-P, whose carbons are those of the original galactose

Role of UDP-galactose in biosynthetic reactions UDP-galactose can serve as the donor of galactose in a number of synthetic pathways, including synthesis of lactose, glycoproteins, glycolipids, & glycosaminoglycans Note: if galactose is not provided by the diet (e.g., when it can’t be released from lactose as a result of a lack of β-galactosidase in people who are lactose-intolerant), all tissue requirements of UDP-galactose can be met by the action of UDP-hexose 4-epimerase on UDP-glucose, which is efficiently produced from G-1-P UTP+G-1-p  UDP-glu, UDP-glucose pyrophosphorylase

Metabolism of galactose.

E. Disorders of galactose metabolism Galactose 1-phosphate uridyltransferase is missing in individuals with classic galactosemia. In this disorder, galactose 1-P &, therefore, galactose, accumulates in cells. Physiologic consequences are similar to those found in fructose intolerance, but a broader spectrum of tissues is affected. The accumulated galactose is shunted into side pathways such as that of galactitol production. This reaction is catalyzed by aldose reductase, the same enz that converts gluc to sorbitol Note: a more benign form of galactosemia is caused by a deficiency of galactokinase

Lactose synthesis Lactose is a disacch that consists of a molecule of β-galactose attached by β(1→4) linkage to gluc. Therefore, lactose is galactosyl β(1→4)-glucose. Lactose, known as “milk sugar”, is produced by mammary glands of most mammals. Therefore, milk & other dairy products are the dietary sources of lactose. Lactose is synthesized in the ER by lactose synthase (UDP-galactose:glucose galactosyltransferase), which transfers galactose from UDP-galactose to gluc, releasing UDP.