number Done by Corrected by Doctor Nayef Karadsheh

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1 number 16 Done Huda shaheen by Corrected by حسام أبو عوض Doctor Nayef Karadsheh 1

2 In the previous lecture, we talked about glycogen metabolism and regulation. In this sheet we will talk about the metabolism of monosaccharides and disaccharides, which is explained in chapter 12 in Lippincott textbook. - Sugars can be interconverted to each other; glucose can convert to fructose, mannose and galactose. - Remember that Glucose is the most common monosaccharide consumed by humans. In this lecture we will talk about fructose, mannose and galactose. We will discuss their metabolism, interconversion and the most important genetic disorders affecting them that may cause diseases in our bodies. Let's start with the first monosaccharide, fructose: NOTES. If you eat normal amounts of fructose not excess and not low amounts -, that will give you about 10% of your calories needs. Fructose constitutes half the amount of table sugar, which we use to sweeten food. Fructose is found as a free monosaccharide in honey, many fruits and in high-fructose corn syrup (typically 55% fructose and 45% glucose). corn syrup is used in industry to sweeten soft drinks and other products. We can get this syrup by hydrolysis of starch and isomerization of the half of glucose, so we get 50% fructose and 50% glucose. The major source of fructose is the disaccharide sucrose, which when cleaved in the intestines by sucrase (sucrase cleaves the alpha-1,2- glyosidic bond) releases equimolar amounts of fructose and glucose. Fructose transport into cells is not insulin dependent (unlike that of glucose in certain tissues) and, in contrast to glucose, fructose does NOT promote the secretion of insulin. FRUCTOSE METABOLISM A-Phosphorylation 2

3 For fructose to enter the pathways of intermediary metabolism, it must first be phosphorylated. o This can be accomplished by either hexokinase or fructokinase. Hexokinase It has low affinity (a high Michaelis constant [Km]) for fructose. (its affinity is higher for glucose) Therefore, unless the intracellular concentration of fructose becomes unusually high, the normal presence of saturating concentrations of glucose means that little fructose is being phosphorylated by hexokinase. Fructokinase rimary mechanism for fructose phosphorylation enzyme has a low Km for fructose and high Vmax. It is found in the liver* (which processes most of the dietary fructose), kidney* and the small intestinal mucosa*. Its function is to convert fructose to fructose 1-phosphate using ATP. *Note: These three tissues also contain aldolase B, which is involved in the second phase of fructose metabolism. B. Cleavage of fructose-1-phosphate Fructose-1-phosphate Is NOT converted to fructose-1,6-bisphosphate in the same manner it is in glucose metabolism. Here it is cleaved by aldolase B (also called fructose-1-phosphate aldolase) to two trioses: dihydroxyacetone phosphate (DHAP) and glyceraldehyde. Glyceraldehyde is then phosphorylated by the enzyme triose kinase to glyceraldehyde-3-phosphate(g3p). This G3P then interacts with DHAP to form fructose-1,6-bisphosphate, which is used in gluconeogenesis to produce glucose. (both DHAP and G3P can be produced directly from fructose-1,6-bisphosphate by the action of 3 enzymes: Aldolase A, B or C*) *Note: Humans express three aldolases, A, B and C; the products of three different genes. Aldolase A (found in most tissues), aldolase B (liver, kidney and small intestines) and aldolase C (in brain) all cleave fructose-1,6-bisphosphate produced during glycolysis to DHAP and glyceraldehyde-3-phosphate, but only aldolase B cleaves fructose 1-phosphate. glyceraldehyde has two pathways: 3

4 1- It can convert to glyceraldehyde-3-phosphate by triose kinase requiring use of an ATP molecule. Then this glyceraldehyde-3-phosphate is either converted to pyruvate or to dihydroxyacetone Phosphate by triose phosphate isomerase. This dihydroxyacetone phosphate is converted to glycerol-3-phosphate by glycerol-3-phosphate dehydrogenase, and this reaction requires the use of NADH/+H. finally we get either phosphoglycerides or triacylglycerols. 2- It can be converted to glycerol by alcohol dehydrogenase and by adding NADH/+H, then from Glycerol we can get glycerol-3-phosphate through an enzyme called glycerol kinase, this reaction requires ATP. Finally, we get either phosphoglycerides or triacylglycerols. LOOK AT the following figure, it illustrates the pathways mentioned before. 4

5 D. Disorders of fructose metabolism: There are two types of disorders; one is common the other is rare. 1.Fructokinase deficiency (Essential fructosuria): Extremely rare; one person per 100 thousand has it (1:100000). This deficiency does not cause any clinical symptoms; the fructose is simply excreted in the urine or is 5

6 metabolised to fructose-6-phosphate by alternate pathways in the body. A person who always consumes sugary products but doesn t gain any weight can be said to have fructokinase deficiency. 2.Aldolase B deficiency (Hereditary Fructose Intolerance [HFI]): Causes severe disturbance of liver and kidney metabolism and is estimated to occur in 1:20,000 live births. The first symptom of HFI appears when a baby is weaned from milk and begins to be fed food containing sucrose or fructose. Fructose-1- phosphate then accumulates, resulting in a drop in the level of inorganic phosphate (Pi) and as a result ATP production. As ATP levels fall, Adenosine Monophosphate (AMP) rises. The AMP is then degraded, causing hyperuricemia, lactic acidosis, hemorrhage, hepatomegaly, hypoglycemia, jaundice and vomiting. Diagnosis of HFI can be made based on fructose in the urine, enzyme assay using liver cells or by DNA-based testing. *If a baby is constantly vomiting after consumption of food containing sucrose or fructose, it is relatively easy to recognize the possibility of Aldolase B deficiency. The symptoms can be reduced by eliminating such food from the baby s diet. Aldolase B deficiency is part of the new-born screening panel. With HFI, sucrose-as well as fructose-must be removed from the diet to prevent liver failure and possible death. Individuals with HFI display an aversion to sweets and, consequently, have an absence of dental caries. B-Conversion of mannose to fructose-6-phosphate - Mannose, the C-2 epimer of glucose, is an important component of glycoproteins and glycolipids. - Hexokinase phosphorylates mannose, producing mannose-6-phosphate, which in turn is reversibly isomerized to fructose-6-phosphate by 6

7 phosphomannose isomerase. This figure illustrates the conversion of glucose to fructose; there is an enzyme present in certain cells called aldose reductase; it converts glucose to sorbitol (also called polyol), then by sorbitol dehydrogenase the sorbitol is oxidized to fructose. Aldose reductase is found in many tissues: retina, lens, kidney, peripheral nerves, ovaries and seminal vesicles. BUT sorbitol dehydrogenase is not found in the retina, lens, peripheral nerves or the kidney. It is present in the liver, seminal vesicles and ovaries. This enzyme is very important to seminal vesicles to support the sperms by fructose as it provides more energy for them. If you read the labels of some Industrial products, you will notice that there is sorbitol >> oxidized to fructose. In diabetic people, when glucose concentration is high**>> part of this glucose will be converted to sorbitol >> when sorbitol concentration is high, it is converted in the liver to fructose. BUT the problem of sorbitol being present in high concentration is that the clearance of it becomes very low. This high concentration increases osmotic pressure >> increases intake of water >> resulting in swelling then damage to the cell. So, people who have chronic diabetes may suffer from complications including cataract formation, peripheral neuropathy and microvascular problems which can lead to nephropathy and retinopathy. <-NOTE -> Use of NADPH in the aldose reductase reaction decrease the the generation of reduced glutathione, which is an important antioxidant. **All cells that were discussed here are not insulin-dependent (Skeletal muscle and adipose tissue are). In the liver insulin helps in storing glycogen and in glycolysis too. 7

8 GALACTOSE METABOLISM Galactose is an isomer of glucose; specifically, it is an epimer of glucose (C4 epimer) the only difference between them is around carbon number 4 The most important source of it is lactose in milk, the digestion of which is carried out by β-galactosidase enzyme (lactase) in the intestinal mucosal cell membrane. Some galactose can also be obtained by lysosomal degradation of complex carbohydrates, such as glycoproteins and glycolipids, which are important membrane components. Like fructose, the transport of galactose into cells is not insulin dependent. some people have lactase deficiency, so how do they get galactose? By converting glucose to galactose or vice versa. we will discuss this topic next. - UDP galactose is a compound of( UDP+GALACTOSE) and it is important for galactose metabolism. (we said previously that for the sugar to become activated it should to be linked to a UDP molecule (UDP-GLUCOSE, UDP-MANNOSE etc)). To understand the metabolism of galactose process please follow this figure: 8

9 Phosphorylation of galactose: Like fructose, galactose must be phosphorylated before it can be further metabolized. Most tissues have a specific enzyme for this purpose: galactokinase, which produces galactose-1-phosphate. As with other kinases, ATP is the phosphate donor. # galactokinase is present in several tissues. Unlike fructokinase which is present in certain tissues only. A reaction between galactose-1-phosphate and UDP-glucose takes place, in which each one gives its functional group to the other. This is a reversible reaction. This reaction is of extreme importance for individuals who suffer from lactase deficiency; galactose is normally obtained by metabolizing lactose into glucose and galactose through the enzyme lactase. But in the case of its deficiency this process is not carried out. So, galactose is obtained by this reaction. UDP-galactose can also give us glycolipid, glycoprotein and glycosaminoglycans when we need them. 9

10 DISORDERS *The most important enzyme here is GALT (Galactose-1-phosphate uridyl transferase). *GALT is deficient in individuals with classic galactosemia. In this disorder, galactose-1-phosphate is not metabolized and as a result galactose accumulates. Physiologic consequences are like those found in hereditary fructose intolerance(hfi), but a broader spectrum of tissues is affected here. The accumulated galactose is shunted into side pathways such as that of galactitol production. This reaction is catalysed by aldose reductase, the same enzyme that reduces glucose to sorbitol. Treatment requires removal of galactose and lactose from the diet. GALT deficiency is part of the new-born screening panel. *: A deficiency in galactokinase results in a less severe case of galactosemia in which cataracts are common. When this happens, aldose reductase reduces galactose into galactitol also called sorbitol. This galactitol is large and cannot exit the cell, causing water to be absorbed into it leading to cataract formation. NOW we finished talking about monosaccharides. let's talk about disaccharides (LACTOSE) Lactose is a disaccharide that consists of a β-galactose molecule attached by a β (1 4) linkage to a glucose molecule. Lactose (known as milk sugar) is made by lactating (milk producing) only in mammary glands. Lactose synthesis The enzyme involved in this process is a complex of two proteins; the first protein is called protein A (β-d-galactosyltransferase). This enzyme is present in most cells.. It transfers galactose from UDP-galactose to N-acetyl-D-glucosamine, forming the β (1 4) linkage found in lactose, and producing N-Acetyllactosamine, a 10

11 component of the structurally important N-linked glycoproteins. Protein B is found only in lactating mammary glands. It is an α-lactalbumin, and its synthesis is stimulated by the peptide hormone prolactin. Protein B forms a complex with the enzyme protein A, changing the specificity of that transferase so that lactose is produced. 11