Carbohydrate metabolism

Chapter 17

Carbohydrate metabolism

Carbohydrates occupy an important place in metabolism because of their roles in energy production and various biosynthetic pathways. Starch is the main source of energy in most populations (page 122) and before it can be absorbed it must be broken down. The hydrolysis of starch is catalysed by enzymes known as amylases which occur in the saliva and the pancreatic juice. The amylases of animal origin are called α-amylases in order to distinguish them from the β-amylases of plants, which differ in their point of attack on the starch molecule. The β-amylases are exoamylases which nip off maltose units from the ends of the amylose and amylopectin molecules, whereas the α-amylases are endoamylases and catalyse the breakdown of bonds occurring in the interior of the molecules. The first products of the action of the α-amylases are the dextrins (page 98) which are progressively degraded into smaller and smaller units. The final product consists mainly of maltose together with some small branched-chain oligosaccharides. A separate enzyme produced in the intestine is required to hydrolyse the α-1:6 bonds of amylopectin.

The amylase present in saliva is unlikely to have a significant digestive function in Man because of the short time during which the food is in the mouth and the fact that the gastric pH (1−2) is well below the optimum pH (6·8) of salivary amylase. It is likely, therefore, that the breakdown of starch is mainly effected in the small intestine by pancreatic amylase. The α-amylases require Cl as a cofactor whereas most ionic cofactors are cations.

The dietary carbohydrates also include sucrose and lactose. Specific disaccharidases which convert these sugars into their constituent monosaccharides are present in the brush border of the intestinal epithelial cells. Only monosaccharides can be absorbed and an active transport system ensures that glucose, galactose and other sugars having the structural features shown below

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are absorbed even against a concentration gradient. The active transport of such sugars into the mucosal cells is linked with the transport of Na+ in the same direction. Other monosaccharides including fructose and the pentoses are absorbed by passive means. The monosaccharides pass into the portal system and are transported to the liver, where they are converted into compounds that are normal intermediates of glucose metabolism.

Glucose breakdown

Three distinct but integrated pathways are responsible for the breakdown of glucose and its conversion to carbon dioxide, water and utilizable energy. They are: (1) the glycolytic or Embden-Meyerhof pathway; (2) the citrate cycle and electron-transport chain which provide the final common pathway for the products of carbohydrate, lipid and amino acid metabolism; (3) the pentose phosphate pathway.

The glycolytic or Embden-Meyerhof pathway

The process of glycolysis, whereby glucose is converted to pyruvate and a small amount of ATP is produced, occurs in the cytoplasm and is essentially the same in all living cells regardless of whether the organism is an aerobe or an anaerobe. Variations occur, however, in the subsequent metabolism of the pyruvate.

The intermediates in glycolysis are all phosphorylated derivatives of hexose (C6) or triose (C3) sugars and the first three steps in the pathway convert the glucose into a form that can be broken down into two triose phosphate units.

Reaction 4

At this stage fructose 1,6-bisphosphate is cleaved to give two triose phosphate molecules, namely glyceraldehyde 3-phosphate and dihydroxyacetone phosphate in a reversible reaction which is catalysed by aldolase.

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Because of the presence of triose phosphate isomerase the glyceraldehyde 3-phosphate and dihydroxyacetone phosphate are interconvertible. Glyceraldehyde 3-phosphate is on the direct pathway of glycolysis (Figure 17.1) and is continuously removed with the result that dihydroxyacetone phosphate is continuously converted into glyceraldehyde 3-phosphate. Not all the dihydroxyacetone phosphate is used in this way; some is converted to α-glycerophosphate which takes place in the α-glycerophosphate shuttle (page 230) and some may be used in the synthesis of triglycerides. However, when considering the oxidation of glucose it may be assumed that each molecule will give rise to two molecules of glyceraldehyde 3-phosphate which will both participate in the subsequent reactions.

Reaction 5

Up to this point two molecules of ATP have been used in the reaction sequence and no energy has been extracted from it. The next reaction, however, involves an oxidation in which the aldehyde group of the glyceraldehyde 3-phosphate is both dehydrogenated and phosphorylated and converted into the high-energy compound 1,3-diphosphoglycerate which is a mixed anhydride of a carboxylic acid and phosphoric acid. The energy required for this conversion comes from the oxidation of the aldehyde group and enables inorganic phosphate to act as the donor. The hydrogen atoms that are removed are transferred to the hydrogen-carrying

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coenzyme NAD+. The reaction is blocked by iodoacetate which combines with an −SH group of the enzyme glyceraldehyde 3-phosphate dehydrogenase and interferes with the substrate binding.

Energy production and the importance of glycolysis

During the conversion of one molecule of glucose to two molecules of pyruvate, two molecules of ATP are used to prime reactions 1 and 3 but, since reactions 5−9 occur twice over, for every molecule of glucose metabolized, a total of four molecules of ATP are produced, two each in reactions 6 and 9, giving a net synthesis of two molecules of ATP. Thus the overall reaction is

Glucose+2Pi+2ADP+2NAD+2pyruvate+2ATP+2NADH+2H+

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Pyruvate is an important compound. After entering the mitochondria it may be converted to acetyl-CoA (page 232) which is then oxidized to carbon dioxide and water by the joint activities of the citrate cycle and electron-transport chain with the production of much greater quantities of ATP than are produced by glycolysis alone. It also has a role in amino acid synthesis as it may be transaminated to form alanine (page 281). Pyruvate is also an important intermediate in gluconeogenesis the process whereby glucose is synthesized from non-carbohydrate sources (page 237). In bacteria a variety of end products may be formed from pyruvate depending both on the nature of the bacterium and the environmental conditions. When oxygen is in short supply, muscle tissue converts pyruvate to lactate while yeasts ferment it to ethanol.

The three-dimensional structures of seven glycolytic enzymes, three dehydrogenases, three kinases and a mutase have been worked out. All of them, in spite of the diversity of the reactions they catalyse, contain a region which has a similar structural pattern in which 150 amino acids take part. This suggests that all these enzymes are derived from a common primeval gene and that the glycolytic pathway must have developed at a very early stage in evolution.

Aerobic and anaerobic glycolysis

During the oxidation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate, which is the only oxidative step in the glycolytic pathway, NAD+ is converted into its reduced form (NADH) and, unless there is a continuous supply of NAD+, the oxidation of glyceraldehyde 3-phosphate will cease. Glycolysis takes place in the cytoplasm and it is here that NADH must be oxidized to NAD+. However, the enzymes specifically responsible for this reaction are constituents of the electron-transport chain and are localized in the mitochondria. A simple solution would appear to be that NADH should pass into the mitochondria and, after oxidation to NAD+ should return to the cytoplasm. The mitochondrial membrane is not, however, readily permeable to NADH and NAD+; this complication is overcome by oxidizing NADH to NAD+ at the expense of dihydroxyacetone phosphate which is reduced to glycerol 3-phosphate. The enzyme catalysing the reaction is glycerol 3-phosphate dehydrogenase. The glycerol 3-phosphate then passes into the mitochondria where it is reoxidized to dihydroxyacetone phosphate. The dehydrogenase which catalyses the conversion of glycerol 3-phosphate to dihydroxyacetone phosphate in the mitochondria is different from the NAD+-linked glycerol 3-phosphate dehydrogenase present in the cytosol. It is linked to FAD instead of NAD+ and transfers electrons to the respiratory chain at the level of coenzyme Q (page 216). Consequently only two molecules of ATP, instead of three, are formed when cytoplasmic NADH is oxidized in this way. The dihydroxyacetone phosphate returns from the mitochondria to the cytoplasm where it is once again available to participate in the oxidation of NADH, thus permitting the oxidative step in aerobic glycolysis to proceed. This is known as the glycerophosphate shuttle.

Glucose+2Pi+2ADP+2NAD+2pyruvate+2ATP+2NADH+2H+

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Another way in which reducing power may be transferred across the mitochondrial membrane is by means of the malate−oxaloacetate shuttle. The cytoplasmic NADH is used to reduce oxaloacetate to malate which, unlike oxaloacetate, is able to pass into the mitochondrion. Having done so it is reconverted to oxaloacetate with the formation of mitochondrial NADH. The oxaloacetate is returned to the cytoplasm in the form of aspartate.

Glucose+2Pi+2ADP+2NAD+2pyruvate+2ATP+2NADH+2H+

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Anaerobic glycolysis in muscle

When glycolysis is occurring under aerobic conditions the hydrogen atoms released in the oxidative reaction take the pathway shown above and are oxidized to water via the reactions of the electron-transport chain. However, when, as in a muscle that is being strenuously exercised, there is a shortage of oxygen, the mitochondrial system, which is essentially aerobic, cannot operate effectively and an alternative method must be found to oxidize the NADH produced during glycolysis. Under these conditions, instead of the NADH being used to convert dihydroxyacetone phosphate into glycerophosphate, it is used to convert pyruvate into lactate by the following reaction which is catalysed by lactate dehydrogenase:

CH3·CO·COOH+NADH+H+Lactate dehydrogenaseCH3·CHOH·COOH+NAD+

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In this way NAD+ is regenerated and the muscle cells can continue to produce small amounts of ATP glycolytically. ATP may also be derived from phosphocreatine and from the myokinase reaction.

Quite large amounts of lactate may be produced in muscle as a result of anaerobic glycolysis and its fate is considered later (page 239). It is mainly derived from muscle glycogen since, although when resting the muscles obtain their energy by metabolizing glucose and fatty acids obtained directly from the blood, during exercise the stored muscle glycogen is called upon. This has the advantage that, at a time when ATP is in short supply, one molecule is ‘saved’ for every glucosyl residue of glycogen used instead of glucose itself. This is because the glucosyl residues are in a higher energy state than free glucose and are phosphorylated by a low-energy phosphoryl donor, i.e. inorganic phosphate (page 234) rather than ATP, which is needed for the phosphorylation of glucose.

Anaerobic glycolysis in yeast

In yeast the enzyme pyruvate decarboxylase catalyses the decarboxylation of pyruvate to CO2 and acetaldehyde. Pyruvate decarboxylase requires Mg2+ and thiamine pyrophosphate as a coenzyme. The acetaldehyde is then reduced to ethanol in a reaction catalysed by alcohol dehydrogenase in which the NADH produced during glycolysis is oxidized and NAD+ is regenerated

CH3·CO·COOHMg2+,TPPPyruvatedecarboxylaseCH3·CHO+CO2CH3·CHOAcetaldehyde+NADH+H+AlcoholdehydrogenaseCH3·CH2OHEthanol+NAD+                                                             

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The net reaction for the fermentation of glucose is

Gulcose+2Pi+2ADP2ethanol+2CO2+2ATP

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Other microorganisms have different ways of metabolizing pyruvate. End products include lactic acid, butyric acid and propionic acid as well as various alcohols. Some of the reactions are considered in more detail in connection with the metabolism of plaque.

Conversion of pyruvate to acetyl-CoA

Glycolysis is linked to the citrate cycle (page 240) by a series of reactions in which pyruvate is converted into the acetyl derivative of coenzyme A. Coenzyme A has a nucleotide-type

Gulcose+2Pi+2ADP2ethanol+2CO2+2ATP

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Dec 10, 2015 | Posted by in General Dentistry | Comments Off on Carbohydrate metabolism
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