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

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

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Metabolism of monosaccharides and disaccharides

Galactose and fructose metabolism as part of the essential pathways of energy metabolism.OverviewAlthough 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 monosacchs, 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 CHOs

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 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.GalactoseGalactose 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...LiverMuscleAdiposeGalactoseFructoseConversion to glucoseGlucose

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

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 glycolysisNote: loading the liver with fructose, e.g., by intravenous infusion, can significantly elevate the rate of lipogenesis caused by enhanced production of acetyl CoA Kinetics of fructose metabolismA deficiency of one of the key enzs 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

Disorders of fructose metabolism11Pi levels fall because Pi is trapped in F-1-P

A deficiency of one of the key enzs 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.

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 occurDiagnosis of HFI can be made on basis of fructose in urine.hereditary fructose intolerance

15Figure 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 glycoproteinsHexokinase phosphorylates mannose mannose 6-P, which in turn, is (reversibly) isomerized to F-6-P by phosphomannose isomeraseNote: there is little mannose in dietary CHOs. Most intracellular mannose is synthesized from fructose, or is pre-existing mannose produced by degradation of structural CHOs & 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 Ps cant freely cross membs without specific transportersAn 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

Sorbitol metabolism

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 gluconeogenesisThe 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 concs & an adequate supply of NADPH cause aldose reductase to produce a sufficient increase in the amount of sorbitol, which cant 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 retentionSome 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 21including the lens, retina, Schwann cells of peripheral nerves, liver, kidney, placenta, RBCs, & cells of the ovaries & seminal vesicles.

Elevated intracellular gluc concs & an adequate supply of NADPH cause aldose reductase to produce a sufficient increase in the amount of sorbitol, which cant 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 retentionGalactose metabolism

The major dietary source of galactose is lactose (galactosyl 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 cant 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