Module 4: Carbohydrate metabolism

Question 1

Metabolism of Nutrients: An Overview

KEY CONCEPTS

Answer 1

Anabolic pathways are building pathways, in which new, usually larger, molecules are made from smaller molecules.
Catabolic pathways are breakdown pathways, in which larger molecules are broken down into smaller molecules.
Metabolism consists of all of the anabolic and catabolic pathways, and these pathways require nutrients to proceed.
Adenosine triphosphate (ATP) is the main molecule used to provide energy to metabolic pathways in the cell. It is often referred to as the energy “currency” of the cell.

Question 2

Anabolic and Catabolic Pathways

Answer 2

Depending on the body’s needs, the glucose, fatty acids, and amino acids absorbed from the diet are broken down to provide energy, used to synthesize essential structural or regulatory molecules, or transformed into energy-storage molecules. The conversion of one molecule into another often involves a series of reactions. The series of biochemical reactions needed to go from a raw material to the final product is called a metabolic pathway. For each of the reactions of a metabolic pathway to proceed at an appropriate rate, an enzyme is required. These enzymes often need help from coenzymes. Coenzymes are molecules that an enzyme will bind and use in a reaction. Many vitamins are essential coenzymes in the body, and the B vitamins are especially important coenzymes in energy metabolism.

Question 3

Producing ATP

Answer 3

Inside cells, glucose, fatty acids, and amino acids derived from carbohydrates, fats, and proteins, respectively, can be broken down in the presence of oxygen to produce carbon dioxide and water. These reactions release energy that is used to add a phosphate group to adenosine diphosphate (ADP) to form ATP. This catabolic pathway is called cellular respiration. In cellular respiration, oxygen brought into the body by the respiratory system and delivered to cells by the circulatory system is used and carbon dioxide is released. This carbon dioxide is then transported to the lungs, where it is eliminated in exhaled air.

Question 4

Synthesizing New Molecules

Answer 4

Glucose, fatty acids, and amino acids that are not broken down for energy are used in anabolic pathways to synthesize structural, regulatory, or storage molecules. Glucose molecules can be used to synthesize glycogen, a storage form of carbohydrate. If the body has enough glycogen, glucose can also be used to synthesize fatty acids. Fatty acids can be used to synthesize triglycerides that are stored as body fat. Amino acids can be used to synthesize the various proteins that the body needs, such as muscle proteins, enzymes, protein hormones, and blood proteins. Excess amino acids can be converted into fatty acids and stored as body fat.

In the following chapters, we will explore the pathways of cellular respiration in more detail, as well as discuss how glucose is utilized when oxygen is absent, how it is regulated in the body, and how disruptions in these processes can lead to disease.

Question 5

Carbohydrate Structure and Transport

KEY CONCEPTS

Answer 5

Carbohydrates are molecules made of exclusively carbons, oxygen, and hydrogen, and they are known as sugars or saccharides.
Carbohydrates exist as monomers, known as monosaccharides, as well as polymers. Small polymers with two sugar molecules are known as disaccharides, while large polymers are called polysaccharides or complex carbohydrates. The linkages of the polysaccharides determine whether they are digestible by humans or not.
Glucose and other monosaccharides enter the cell via a transport protein known as Glut4. The glucose is then phosphorylated to keep it within the cell.

Question 6

Carbohydrate Structure

Answer 6

Carbohydrates are molecules that are made up of equal parts carbon (“carbo”) and water (“hydrate”). Thus, their formula is always CxH2xOx, with the number of carbon and oxygen atoms being equal and the number of hydrogen atoms being twice that of the carbon/oxygen atoms. They make up the bulk of the human diet and are important sources of energy. Additionally, carbohydrates are used as structural materials for a variety of cellular components. There are both simple and complex carbohydrates in our diet. The simple carbohydrates are often referred to as sugars and include both monosaccharides and disaccharides. Large, more complex carbohydrates are polysaccharides. Most carbohydrates have names that end in “-ose”, such as glucose, sucrose, or cellulose.

Question 7

Carbohydrate Transport into Cells

Answer 7

Carbohydrates make up a significant portion of the human diet, both in the simple form of mono- or disaccharides, or as the complex carbohydrates found in starchy foods, such as bread. After ingestion, digestion of carbohydrates takes place mainly in the small intestine. The products of digestion are absorbed by the cells in the lining of the intestine. The bulk of the nutrients from carbohydrates reach the liver for further catabolism, storage or release into the bloodstream depending on the energy needs of the system.

Question 8

Carbohydrate Transport into Cells

Answer 8

Carbohydrates make up a significant portion of the human diet, both in the simple form of mono- or disaccharides, or as the complex carbohydrates found in starchy foods, such as bread. After ingestion, digestion of carbohydrates takes place mainly in the small intestine. The products of digestion are absorbed by the cells in the lining of the intestine. The bulk of the nutrients from carbohydrates reach the liver for further catabolism, storage or release into the bloodstream depending on the energy needs of the system.

Question 9

Glycolysis

KEY CONCEPTS

Answer 9

Glycolysis is a series of enzyme-catalyzed steps in which a six-carbon molecule is broken down into two three-carbon pyruvate molecules.
The pathway results in the net production of two ATP and two NADH molecules.
Substrate-level phosphorylation generates the ATP produced by glycolysis.

Question 10

Glycolysis…Biology basics activityAerobic Metabolism: Respiration

KEY CONCEPTS

Answer 10

Pyruvate from glycolysis is converted to a two-carbon molecule called acetyl-CoA in the matrix of the mitochondria.
The citric acid cycle is a cycle of eight enzymatic reactions that convert acetyl-CoA to CO2 and transfers the electrons to the electron carrying molecules NADH and FADH2.
The NADH and FADH2 from the citric acid cycle donate their electrons to the electron tranport chain, which uses the energy from the electron transfers between multiple protein complexes to generate a proton (hydrogen ion) gradient inside the mitochondria.
Oxygen is the terminal electron acceptor that ultimately receives the electrons from the electron transport chain. Upon accepting the electrons, oxygen combines with protons to create water. The role of oxygen is crucial for the generation of ATP in the cell and is the sole use of the oxygen we breathe.
ATP synthase uses the proton gradient created by the electron transport chain to generate ATP from ADP and phosphate in a process known as oxidative phosphorylation.

Question 11

Pyruvate is Converted to Acetyl-CoA in the Matrix

Answer 11

Carbohydrate metabolism begins with glycolysis to create two molecules of pyruvate for each glucose molecule that enters. The fate of this pyruvate depends on whether or not oxygen is present. The fate of pyruvate under anaerobic conditions will be discussed in the next chapter. Under aerobic conditions (when oxygen is present), the pyruvate is converted to acetyl-CoA and enters the citric acid cycle, which then feeds electron carriers to the electron transport chain to create ATP.

Question 12

The Citric Acid Cycle is Central to Aerobic Metabolism

Answer 12

The citric acid cycle, named for the first intermediate formed in the cycle, metabolizes two-carbon units, known as acetyl groups, to CO2 and H2O. It is also called the Krebs cycle, named for the German biochemist Hans Krebs, who identified its steps in the late 1930s. Both names are frequently used. The video below discusses why the citric acid cycle is central to aerobic metabolism.

Question 13

Summary of Cellular Respiration

Answer 13

TP is the cell’s energy currency, and is used for a myriad of processes in the cell. When we ingest food, the nutrients are broken down and eventually form acetyl-CoA for entry into cellular respiration. Fatty acids are converted to acetyl-CoA via beta oxidation (a process covered in detail in the next module), amino acids (depending on which one) are converted to acetyl-CoA directly or via pyruvate, and sugars such as glucose are processed via glycolysis to pyruvate, which is then converted to acetyl-CoA. While glycolysis produces a net of 2 ATP per glucose molecule, it is the NADH generated during the reactions of the citric acid cycle that ultimately produces the majority of the ATP needed by the cell.

A schematic depiction of the principal reactions of cellular respiration is presented here:

Question 14

Anaerobic Metabolism: The Cori Cycle

Answer 14

Thus far, we have discussed the conversion of carbohydrates (mainly glucose) to ATP in the presence of oxygen. While this is certainly the most common fate of glucose in the body, there are instances in which cells must use glucose to produce ATP without the aid of aerobic respiration. This section deals with these conditions.

Question 15

The Fates of Pyruvate

Answer 15

As you saw in the Biology Basics animation on glycolysis, the fate of pyruvate produced during glycolysis depends on the availability of oxygen. When oxygen is abundantly present, pyruvate will be converted to acetyl-CoA and enter cellular respiration to make ATP.

Question 16

The Cori Cycle

Answer 16

As discussed above, cells can convert pyruvate to lactate under anaerobic conditions to allow glycolysis to continue producing some ATP. Some of the lactate produced as a result of fermentation can be converted back to pyruvate and enter cellular respiration. However, this process can only happen when the cell is no longer anaerobic, and it cannot happen in RBCs, which lack mitochondria. Under anaerobic conditions in most cells, or continually in RBCs, the lactate is eventually converted back to glucose in a process known as the Cori cycle (or glucose-lactate cycle) (Figure 4-16).

In the Cori cycle, lactate produced by fermentation leaves the cell and enters the blood. The liver cells take up the lactate from the blood and use the gluconeogenesis pathway to convert two molecules of lactate back to glucose. This glucose is then released back into the blood for transport back to the cells. This cycle provides for a continuous supply of glucose to tissues that require it as their primary energy source, such as RBCs.

Question 17

Glucose Production and Storage

KEY CONCEPTS

Answer 17

Glucose can be built from noncarbohydrate sources by gluconeogenesis.
Glucose is stored in the form of glycogen.
Glycogenesis is a process of building glycogen from glucose units.
Glycogenolysis is the breakdown of the glycogen polymer to release individual glucose units.
In addition to generating ATP, glucose may take part in or be formed by several anabolic reactions. One is the synthesis of new glucose molecules from some of the products of protein and fat breakdown; another is the synthesis of glycogen.

Question 18

Formation of Glucose from Proteins and Fats: Gluconeogenesis

Answer 18

When your body runs low on glucose, it is time to eat. If you don’t, your body starts catabolizing triglycerides (fats) and proteins. Actually, the body normally catabolizes some of its triglycerides and proteins, but large-scale triglyceride and protein catabolism does not happen unless you are starving, eating very few carbohydrates, or suffering from a hormonal disorder.

The glycerol part of triglycerides (more on this in the next module on lipids), lactate (recall the Cori cycle), and certain amino acids can be converted in the liver to glucose (Figure 4-17). The process by which glucose is formed from these noncarbohydrate sources is called gluconeogenesis (gluco = glucose, neo = new, genesis = make). About 60% of the amino acids in the body can be used for gluconeogenesis. Lactate and amino acids such as alanine and serine are converted to pyruvate, which then may be synthesized into glucose or enter the citric acid cycle. Glycerol may be converted into glyceraldehyde 3-phosphate, which may continue on in glycolysis to make pyruvate or be used to synthesize glucose via gluconeogenesis.

Gluconeogenesis is essentially a reversal of the glycolysis pathway because it constructs a glucose molecule from pyruvate, whereas glycolysis breaks down glucose to form pyruvate. Many of the enzymes used in the glycolysis pathway are also used in the gluconeogenic pathway, though there are some enzymes unique to gluconeogenesis that bypass the irreversible steps of glycolysis. For example, the first two enzymes of gluconeogenesis convert pyruvate to oxaloacetate and then phosphoenolpyruvate (PEP) (Figure 4-17), whereas the last step of glycolysis converts PEP directly to pyruvate.

Question 19

Glycogen is a Polymer of Glucose Made by Glycogenesis

Answer 19

If glucose from dietary sources is not needed immediately for ATP production, it combines with many other molecules of glucose to form glycogen, a polysaccharide that is the only stored form of carbohydrate in the body. This polysaccharide is a highly branched polymer that allows for quick addition and removal of the terminal glucose molecules (Figure 4-18). This allows the cells that store glycogen to respond quickly to both glucose need and glucose surplus.

Question 20

Glucose Release: Glycogenolysis

Answer 20

When the cells in the body are low on glucose and require ATP, glycogen stored in hepatocytes is broken down into glucose and released into the blood to be transported to cells, where it will be used in the processes of cellular respiration already described. The process of splitting glycogen into its glucose subunits is called glycogenolysis (glī′-kō-je-NOL-e-sis). (Note: Do not confuse glycogenolysis, the breakdown of glycogen to glucose, with glycolysis, the 10 reactions that convert glucose to pyruvate.)

Question 21

Glycogen Storage Diseases: Tarui Disease

Answer 21

As with many metabolic pathways, disruptions in glucose metabolism can lead to disease. There are several diseases, known as glycogen storage diseases, that involve the unhealthy accumulation of glycogen. One such disease is Tarui disease. Tarui disease is a rare genetic disease caused by a defect in the muscle cell glucose metabolism which manifests as exercise intolerance and excessive glycogen storage. The defective enzyme is phosphofructose kinase (PFK), the third enzyme in the glycolysis pathway that converts fructose-6-phosphate to fructose-1,6-bisphosphate using ATP. A defect in PFK inhibits the production of fructose-1,6-bisphosphate, thus slowing the glycolysis pathway at this point and preventing effective glucose metabolism. As a result, glucose concentrations in the cell increase and stimulate glycogen synthesis and accumulation. A defective glycolysis pathway also results in lowered ATP production and ineffective utilization of carbohydrate food sources, which leads to the observed muscle fatigue.

Question 22

Glucose Regulation and Diabetes

KEY CONCEPTS

Answer 22

Blood glucose levels are controlled by several hormones, predominantly insulin and glucagon.
Insulin is produced in the beta cells of the pancreas and is released in response to increased blood glucose levels, whereas glucagon is produced in the alpha cells of the pancreas and is released in response to low blood glucose levels.
Insulin stimulates the uptake and storage of glucose from the blood by cells in the body. This results in increased glycogenesis as well as fatty acid synthesis. Glucagon stimulates the production of glucose via gluconeogenesis by the liver as well as fatty acid and amino acid catabolism for energy.
Diabetes results from a decreased ability to produce insulin or a decreased sensitivity of cells to the insulin produced by the body (type I and type II, respectively). This leads to excessively high blood glucose levels that are damaging to various organs and systems in the body.
Metformin is one available drug that is able to lower blood glucose by affecting the electron transport chain, gluconeogenesis, and glucose transport into cells.

Question 23

Regulation of Glucose Metabolism

Answer 23

As we have seen, carbohydrate metabolism involves several pathways that can engage in both anabolism and catabolism that requires carefully balanced control to maintain energy levels in the cell. The pancreas is a vital organ in this regulation. Embedded within the pancreas are specialized clusters of cells called the islets of Langerhans, which secrete hormones directly into the blood. The islets include alpha and beta cells. The alpha cells secrete the hormone glucagon when blood glucose levels are low (the name, which sounds like “glucose gone,” suggests its function). Glucagon stimulates liver cells to break down stores of glycogen, releasing glucose into the blood. It also causes the breakdown of glycogen in muscle cells and the production of glucose from amino acids. Glucagon increases blood sugar between meals, supplying energy to the brain and active muscles.

Question 24

Diabetes: Misregulated Glucose Metabolism

Answer 24

Diabetes mellitus, is a well-characterized disorder of glucose metabolism, which affects about 10% of the population of the United States. Worldwide, the disease affects about 350 million people, killing about 3.5 million each year. The words diabetes (meaning “to run through”) and mellitus (“honey”) describe an obvious symptom of the disease. Diabetes results from excessively high levels of blood glucose due to a misregulation of glucose metabolism. Diabetics excrete large amounts of urine containing high concentrations of glucose. The kidneys eliminate excess glucose in the blood by excreting it in urine. This process requires large amounts of water, which explains the strong thirst and urge to urinate excessively associated with the disease.

There are two main types of diabetes. Type 1 diabetes (juvenile-onset or insulin-dependent diabetes) is an autoimmune disease in which the immune system destroys pancreatic beta cells, thus impairing insulin production. Symptoms first appear in childhood as insulin production begins to drop off. Because the disease results from the lack of insulin, it must be treated with insulin supplementation to maintain normal blood glucose levels.

By far the most common form of diabetes, accounting for up to 95% of all cases, is type 2 diabetes (also known as adult-onset or non-insulin-dependent diabetes). These cases are characterized by insulin resistance, which is the failure of the body to respond to normal or even elevated concentrations of insulin.

The insulin resistance in type 2 diabetes is due to changes in the molecular communication that happens in the cell when insulin binds its receptor. As seen in Figure 4-22, under normal circumstances insulin binding will stimulate the translocation of GluT4 receptors to the cell membrane. This effect is carried out via a complex network of cellular signals, and when one or more of the components of this network is impaired, insulin binding no longer produces the same effect on GluT4 translocation. The result is fewer GluT4 receptors to allow glucose to enter the cell, and blood glucose levels stay elevated for longer despite the presence of insulin. In this way, the cells are resistant to insulin and the regulation of glucose metabolism begins to go awry—there is plenty of glucose in the blood, but the cells are not importing it at the same rate. The liver, when insulin resistant, continues to produce (and sometimes overproduce) glucose via gluconeogenesis. The production and release of more glucose by the liver can contribute to the elevated blood glucose levels and exacerbate the situation.

Additionally, insufficient glucose uptake from the blood reduces the amount of pyruvate made by glycolysis. As a result, gluconeogenesis in the liver will instead draw on oxaloacetate (an essential intermediate in the citric acid cycle) to make glucose, thus reducing the ability of cellular respiration to make ATP from non-carbohydrate sources, such as fatty acids. This can lead to diabetic ketoacidosis, as discussed more in the next module on lipids.

Question 25

Glycation: The Danger of High Blood Glucose Levels

Answer 25

The dangers of low blood glucose levels (hypoglycemia) are straightforward: cells in the body need access to glucose to make ATP and carry out their functions and low glucose will prevent cells from having the energy they need. However, what is the danger of high blood glucose levels? Why doesn’t the body use the glucose in the blood as its needed rather than regulating it back down to a normal level? Aside from the osmotic pressure that results from high glucose in the blood (which leads to the intense thirst and frequent urination observed in diabetics), the main long-term danger is from glycation.

Glycation is the reaction in which a covalent bond forms between a sugar molecule and a protein or lipid molecule without the aid of an enzyme. The addition of the sugar can affect the function of a protein by making it more stiff and inflexible. Glycation can also lead to additional reactions that cross-link proteins together into advanced glycation end products (AGEs), which can impair the function of the proteins and their associated organs.

Question 26

Metformin Treats Type 2 Diabetes

Answer 26

Metformin is a commonly prescribed antidiabetic drug to treat non-insulin dependent type 2 diabetes. It is derived from Galega officinalis (French Lilac). The history of the drug can be traced back to medieval times when it was used to relieve symptoms that mimic modern day diabetes. Metformin has been a valuable tool in treating type 2 diabetes because of its effects on blood glucose and as well as other metabolic benefits, such as decreased appetite and weight loss. The ability of metformin to lower blood glucose levels is attributed, in part, to two effects:

Inhibition of gluconeogenesis, thereby lowering glucose production and release by the liver.
Increased translocation of GluT4 transporters to cellular membranes leading to increased glucose uptake by cells in the body, particularly muscle and fat cells.
After consumption of the drug, metformin is taken up by the liver cells, where it enters the mitochondria and binds to complex I of the electron transport chain. This binding decreases the efficiency of this complex is transferring electrons from NADH to coenzyme Q10, thus decreasing the overall production of ATP (Figure 4-24). The reduced ATP production, as well as other effects of the complex I inhibition, acts as a signal to the liver cells (via various pathways still under investigation) to decrease gluconeogenesis.

Question 27

Metformin Treats Type 2 Diabetes

Answer 27

Metformin is a commonly prescribed antidiabetic drug to treat non-insulin dependent type 2 diabetes. It is derived from Galega officinalis (French Lilac). The history of the drug can be traced back to medieval times when it was used to relieve symptoms that mimic modern day diabetes. Metformin has been a valuable tool in treating type 2 diabetes because of its effects on blood glucose and as well as other metabolic benefits, such as decreased appetite and weight loss. The ability of metformin to lower blood glucose levels is attributed, in part, to two effects:

Inhibition of gluconeogenesis, thereby lowering glucose production and release by the liver.
Increased translocation of GluT4 transporters to cellular membranes leading to increased glucose uptake by cells in the body, particularly muscle and fat cells.
After consumption of the drug, metformin is taken up by the liver cells, where it enters the mitochondria and binds to complex I of the electron transport chain. This binding decreases the efficiency of this complex is transferring electrons from NADH to coenzyme Q10, thus decreasing the overall production of ATP (Figure 4-24). The reduced ATP production, as well as other effects of the complex I inhibition, acts as a signal to the liver cells (via various pathways still under investigation) to decrease gluconeogenesis.