6.2: Sugar Metabolism

Starch and glycogen are the main energy storage forms of carbohydrates in plants and animals, respectively. To use these sources of energy, cells must break down the polymers to their component monomers: glucose. The glucose is then taken up by cells through transporter proteins in cell membranes. The metabolism of glucose, as well as other six carbon sugars (hexoses) begins with the catabolic pathway called glycolysis. Glycolysis occurs in the cytosol of cells, not on or in the mitochrondria.

The end metabolic products of glycolysis are two molecules of ATP, two molecules of NADH and two molecules of pyruvate (Figure 6.3), which, in turn, can be oxidized further in the citric acid cycle.

 

Just one step of the glycolysis pathway involves the loss/gain of electrons, but the end product of the pathway, pyruvate, can be completely oxidized by aerobic organisms to carbon dioxide (Figure 6.2). Indeed, without production of pyruvate from glucose in glycolysis, a major energy source for aerobic cells would not be available.

Glucose is the most abundant hexose in nature and is traditionally used to illustrate the reactions of glycolysis, but fructose (in the form of fructose-6- phosphate) is also readily metabolized, while galactose can easily be converted into glucose for catabolism in the pathway as well. The end metabolic products of glycolysis are two molecules of ATP, two molecules of NADH and two molecules of pyruvate (Figure 6.3), which can feed into the Citric Acid Cycle.

Anaerobic organisms do not have the metabolic machinery to completely oxidize pyruvate to carbon dioxide. In these organisms, or in organisms that are experiencing a lack of available oxygen, glycolysis provides some metabolic energy and pyruvate is converted to ethanol or lactic acid.

Ethanol fermentation performed by yeasts and bacteria have and have had a huge influence on the production of food and beverage products. Ethanol beverages (beer, wine, and mash for distillled spirits), breads, cheeses, pickles, and cultured dairy products such as yogurt and kefir can all be produced with the help of these fermentation pathways.

Glycolysis includes ten reactions linked in an almost completely linear pathway:

Reaction 1

Glucose gets a phosphate from ATP to make glucose-6-phosphate (G6P) in a reaction catalyzed by the enzyme hexokinase, a transferase enzyme.

Glucose + ATP ⇄ G6P + ADP + H+

Hexokinase is one of three regulated enzymes in glycolysis and is inhibited by one of the products of its action – G6P. Hexokinase has flexibility in its substrate binding and is able to phosphorylate a variety of hexoses, including fructose, mannose, and galactose.

Why phosphorylate glucose?

Phosphorylation of glucose serves two important purposes. First, the addition of a phosphate group to glucose effectively traps it in the cell, as G6P cannot diffuse across the lipid bilayer. Second, the reaction decreases the concentration of free glucose, favoring additional import of the molecule.

Reaction 2

Next, G6P is converted to fructose-6-phosphate (F6P), in a reaction catalyzed by the enzyme phosphoglucose isomerase:

[latex]\ce{G6P ⇄ F6P}[/latex]

 

Reaction 3

[latex]ce{F6P + ATP ⇄ F1,6BP + ADP + H+}[/latex]

The second input of energy occurs when F6P gets another phosphate from ATP in a reaction catalyzed by the enzyme phosphofructokinase-1 (PFK-1 – another transferase) to make fructose-1,6- bisphosphate (F1,6BP). PFK-1 is a very important enzyme regulating glycolysis, with several allosteric activators and inhibitors.

Like the hexokinase reaction the energy from ATP is needed to make the reaction energetically favorable. PFK-1 is the most important regulatory enzyme in the pathway and this reaction is the rate-limiting step. It is also one of three essentially irreversible reactions in glycolysis.

 

Reaction 4

[latex]\ce{F1,6BP ⇄ D-GLYAL3P + DHAP}[/latex]

With the glycolysis pump thus primed, the pathway proceeds to split the F1,6BP into two 3-carbon intermediates. This reaction catalyzed by aldolase is energetically a “hump” to overcome in the glycolysis direction. In order to get over the energy hump, cells must increase the concentration the reactant (F1,6BP) and decrease the concentration of the products, which are D-glyceraldehyde- 3-phosphate (D-GLYAL3P) and dihydroxyacetone phosphate (DHAP).

Reaction 5

[latex]\ce{DHAP ⇄ D-GLYAL3P}[/latex]

In the next step, DHAP is converted to DGLYAL3P in a reaction catalyzed by the enzyme triosephosphate isomerase. At this point, the six carbon glucose molecule has been broken down to two identical units of three carbons each – D-GLYAL3P.

From this point forward each reaction of glycolysis occurs twice for each glucose that has fed into the pathway.

Reaction 6

[latex]\ce{D-GLYAL3P + NAD+ + Pi D-1,3BPG + NADH + H+}[/latex]

Figure 6.9 – Reaction #5 – Triose phosphate isomerase with unstable, toxic intermediate (methyl glyoxal) Image by Ben Carson

In this reaction, D-GLYAL3P is oxidized in the only oxidation step of glycolysis catalyzed by the enzyme glyceraldehyde-3- phosphate dehydrogenase, an oxidoreductase. The aldehyde in this reaction is oxidized, then linked to a phosphate to make an ester – D-1,3-bisphospho-glycerate (D- 1,3BPG). Electrons from the oxidation are donated to NAD+, creating NADH.

NAD+ is a critical constituent in this reaction and is the reason that cells need a fermentation option at the end of the pathway (see below).

Note here that ATP energy was not required to put the phosphate onto the oxidized D-GLYAL3P. The reason for this is because the energy provided by the oxidation reaction is sufficient for adding the phosphate.

Reaction 7

[latex]\ce{D-1,3BPG + ADP ⇄ 3PG + ATP}[/latex]

The two phosphates in the tiny 1,3BPG molecule repel each other and give the molecule high potential energy. This energy is utilized by the enzyme phosphoglycerate kinase (another transferase) to phosphorylate ADP and make ATP, as well as the product, 3-phosphoglycerate (3-PG). This is an example of a substrate-level phosphorylation: ATP is produced as substrate reacts. Such mechanisms for making ATP require an intermediate with a high enough energy to phosphorylate ADP to make ATP.

Since there are two 1,3 BPGs produced for every glucose, the two ATPs produced in this reaction replenish the two ATPs used to start the cycle and the net ATP count at this point of the pathway is zero.

Reaction 8

[latex]\ce{3-PG ⇄ 2-PG }[/latex]

Conversion of the 3-PG intermediate to 2-PG (2- phosphoglycerate) occurs by an important mechanism. An intermediate in this readily reversible reaction (catalyzed by phosphoglycerate mutase – a mutase enzyme) is 2,3-BPG. This intermediate, which is stable, is released with low frequency by the enzyme instead of being con- Figure 6.13 – Two routes to formation of 2,3-BPG Figure 6.14 – 2,3- Bisphosphoglycerate (2,3-BPG) Figure 6.12 – Reaction #8 – Conversion of 3-PG to 2-PG verted to 2-PG. 2,3BPG is important because it binds to hemoglobin and stimulates release of oxygen. The molecule can also be made from 1,3-BPG as a product of a reaction catalyzed by bisphophglycerate mutase (Figure 6.13).

Why does this make sense? Cells which are metabolizing glucose rapidly release more 2,3-BPG and, as a result, get more oxygen, supporting their needs. Notably, cells which are metabolizing rapidly are using oxygen more rapidly and are more likely to be deficient in it.

Reaction 9

[latex]\ce{2-PG ⇄ PEP + H2O}[/latex]

2-PG is converted by enolase (a lyase) to phosphoenolpyruvate (PEP) by removal of water, creating a very high potential energy product.

Reaction 10

[latex]\ce{PEP + ADP + H+ ⇄ PYR + ATP}[/latex]

Conversion of PEP to pyruvate by pyruvate kinase is the second substrate level phosphorylation of glycolysis, creating ATP. This reaction is what some refer to as the “Big Bang” of glycolysis because there is almost enough energy in PEP to stimulate production of a second ATP, but it is not used. Consequently, this energy is lost as heat. If you wonder why you get hot when you exercise, the heat produced in the breakdown of glucose is a prime contributor and the pyruvate kinase reaction is a major source.

Pyruvate kinase is the third and last enzyme of glycolysis that is regulated (see below). The primary reason this is the case is to be able to prevent this reaction from occurring when cells are making PEP while going through a different process, building glucose via the pathway called gluconeogenesis.

Catabolism of other sugars

Though glycolysis is a pathway focused on the metabolism of glucose and fructose, the fact that other sugars can be readily metabolized into glucose means that glycolysis can be used for extracting energy from them as well. Galactose is a good example. It is commonly produced in the produced in the body as a result of hydrolysis of lactose, catalyzed by the enzyme known as lactase (Figure 6.17). Deficiency of lactase is the cause of lactose intolerance.

Galactose enters into glycolysis after a few reactions that convert it into glucose-6-phosphate.

Deficiency of galactose conversion enzymes results in accumulation of galactose (from breakdown of lactose). Excess galactose is converted to galactitol, a sugar alcohol. Galactitol in the human eye lens causes it to absorb water and this may be a factor in formation of cataracts.

 

Pyruvate metabolism

As described in an earlier chapter, pyruvate produced in glycolysis can be oxidized to acetyl-CoA, which is itself oxidized in the citric acid cycle to carbon dioxide. That is not the only metabolic fate of pyruvate, though (Figure 6.23).

Among its other possible fates, pyruvate can be processed anaerobically by fermentation to ethanol (in bacteria and yeasts) or lactic acid (in animals).

 

Specific glycolysis controls

Control of glycolysis and gluconeogenesis is unusual for metabolic pathways, in that regulation occurs at multiple points. For glycolysis, this involves three enzymes:

1. Hexokinase (Glucose ⇄ G6P)

2. Phosphofructokinase-1 (F6P ⇄ F1,6BP)

3. Pyruvate kinase (PEP ⇄ Pyruvate).

 

 

Polysaccharide metabolism

Sugars are metabolized rapidly in the body and that is one of the primary reasons they are used. Managing levels of glucose in the body is very important – too much leads to complications related to diabetes and too little gives rise to hypoglycemia (low blood sugar). Sugars in the body are maintained by three processes – 1) diet; 2) synthesis (gluconeogenesis); and 3) storage. The storage forms of sugars are, of course, the polysaccharides and their metabolism is our next topic of discussion.

Amylose and amylopectin

The energy needs of a plant are much less dynamic than those of animals. Muscular contraction, nervous systems, and information processing in the brain require large amounts of quick energy. Because of this, the polysaccharides stored in plants are somewhat less complicated than those of animals. Plants store glucose for energy in the form of amylose (Figure 6.34) and amylopectin and for structural integrity in the form of cellulose. These structures differ in that cellulose contains glucose units solely joined by β-1,4 bonds, whereas amylose has only α-1,4 bonds and amylopectin has α-1,4 and α-1,6 bonds.

Glycogen

Animals store glucose primarily in liver and muscle in the form of a compound related to amylopectin known as glycogen. The structural differences between glycogen and amylopectin are solely due to the frequency of the α-1,6 branches of glucoses. In glycogen they occur about every 10 residues instead of every 30-50, as in amylopectin (Figure 6.35).

Because glycogen contains so many glucoses, it acts like a battery backup for the body, providing a quick source of glucose when needed and providing a place to store excess glucose when glucose concentrations in the blood rise.

The branching of glycogen is an important feature of the molecule metabolically as well. Since glycogen is broken down from the “ends” of the molecule, more branches translate to more ends, and more glucose that can be released at once.