Outline

1. Outline 22.1 Digestion of Carbohydrates 22.3 Glucose Metabolism: An Overview 22.3 Glycolysis 22.4 Entry of Other Sugars into Glycolysis 22.5 The Fate of Pyruvate 22.6 Energy Output in Complete Catabolism of Glucose 22.7 Regulation of Glucose Metabolism and Energy Production 22.8 Metabolism in Fasting and Starvation 22.9 Metabolism in Diabetes Mellitus 22.10 Glycogen Metabolism: Glycogenesis and Glycogenolysis 22.11 Gluconeogenesis: Glucose from Noncarbohydrates

2. Goals 1. What happens during digestion of carbohydrates? Be able to describe carbohydrate digestion, its location, the enzymes involved, and name the major products of this process. 2. What are the major pathways in the metabolism of glucose? Be able to identify the pathways by which glucose is (1) synthesized and (2) broken down, and describe their interrelationships. 3. What is glycolysis? Be able to give an overview of the glycolysis pathway and its products, and to identify where the major monosaccharides enter the pathway. • What happens to pyruvate once it is formed? Be able to describe the pathways involving pyruvate and their respective outcomes. • How is glucose metabolism regulated, and what are the influences of starvation and diabetes mellitus? Be able to identify the hormones that influence glucose metabolism and describe the changes in metabolism during starvation and diabetes mellitus. • What are glycogenesis and glycogenolysis? Be able to define these pathways and their purpose. • What is the role of gluconeogenesis in metabolism? Be able to identify the functions, substrates, and products of this pathway.

3. 22.1 Digestion of Carbohydrates • The first stage in catabolism is digestion, the breakdown of food into small molecules. • Digestion entails the physical grinding, softening, and mixing of food, as well as the enzyme-catalyzed hydrolysis of carbohydrates, proteins, and fats. • Digestion begins in the mouth, continues in the stomach, and concludes in the small intestine.

4. 22.1 Digestion of Carbohydrates • The products of digestion are mostly small molecules that are absorbed from the intestinal tract. • Nutrient absorption happens through millions of villi that provide a surface area as big as a football field. • Once in the bloodstream, the small molecules are transported into target cells where many are further broken down.

5. 22.1 Digestion of Carbohydrates

6. 22.2 Glucose Metabolism: An Overview • Glucose is the major fuel for your body. It is the preferred fuel for the brain, muscle cells, and red blood cells. • When glucose enters a cell, it is converted to glucose 6-phosphate. • Phosphorylated molecules cannot cross the cell membrane. • Several pathways are available to glucose 6-phosphate.

7. 22.2 Glucose Metabolism: An Overview

8. 22.2 Glucose Metabolism: An Overview • When energy is needed, glucose 6-phosphate proceeds through glycolysis to pyruvate and then to acetyl-coenzyme A, which enters the citric acid cycle. • When cells are well-supplied with glucose, excess glucose is converted to glycogen, the glucose storage polymer, by the glycogenesis pathway, or to fatty acids. • Glucose-6-phosphate can also enter the pentose phosphate pathway, which yields NADPH and ribose 5-phosphate, which is necessary for the synthesis of nucleic acids.

9. 22.3 Glycolysis • Glycolysis is a series of 10 enzyme-catalyzed reactions that breaks down each glucose molecule into two pyruvate molecules, and, in the process, yields two ATP molecules and two NADH molecules.

10. 22.3 Glycolysis

11. 22.3 Glycolysis Step 1 of Glycolysis: Phosphorylation • Glucose is carried in the bloodstream to cells, where it is transported across the cell membrane into the cytosol. • As soon as it enters the cell, glucose is phosphorylated, which requires an energy investment from ATP. • From here on, all pathway intermediates are sugar phosphates and are trapped within the cells because as charged moieties, phosphates cannot cross cell membranes unaided. • The product of Step 1, glucose 6-phosphate, is an allosteric inhibitor for the enzyme for this step (hexokinase), and therefore plays an important role in the elaborate and delicate control of glucose metabolism.

12. 22.3 Glycolysis Step 2 is the isomerization of glucose 6-phosphate to fructose 6-phosphate • The enzyme (glucose 6-phosphate isomerase) converts glucose 6-phosphate (an aldohexose) to fructose 6-phosphate (a ketohexose). • The result is conversion of the six-membered glucose ring to a five-membered ring with a CH2OH group, which prepares the molecule for addition of another phosphoryl group in the next step.

13. 22.3 Glycolysis Step 3makes a second energy investment as fructose 6-phosphate is converted to fructose 1,6-bisphosphate by reaction with ATP. • When the cell is short of energy, ADP and AMP concentrations build up and activate the Step 3 enzyme, phosphofructokinase. • When energy is in good supply, ATP and citrate build up and allosterically inhibit this enzyme.

14. 22.3 Glycolysis Steps 4 and 5 of Glycolysis: Cleavage and Isomerization • Step 4 converts the 6-carbon bisphosphate from Step 3 into two 3-carbon monophosphates, an aldose phosphate and one a ketose phosphate. • Aldolase catalyzes the breakage of the bond between carbons 3 and 4 in fructose 1,6-bisphosphate, and a C=O group is formed.

15. 22.3 Glycolysis Steps 4 and 5 of Glycolysis: Cleavage and Isomerization • The two 3-carbon sugar phosphates produced in Step 4 are isomers that are interconvertible by triose phosphate isomerase. • Only glyceraldehyde 3-phosphate can continue on the glycolysis pathway.

16. 22.3 Glycolysis Steps 6–10 of Glycolysis: Energy Generation • Step 6 is the oxidation of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate by glyceraldehyde 3-phosphate dehydrogenase. • Some of the energy from the exergonic oxidation is captured in NADH. • Step 7 generates the first ATP of glycolysis by transferring a phosphate group from 1,3-bisphosphoglycerate to ADP.

17. 22.3 Glycolysis Steps 6–10 of Glycolysis: Energy Generation • Steps 8 and 9 are an isomerization of 3-phosphoglycerate to 2-phosphoglycerate catalyzed by phosphoglycerate mutase (step 8) followed by dehydration of 2-phosphoglycerate by enolase (step 9). This generates phosphoenolpyruvate, the second energy-providing phosphate of glycolysis. • Step 10 is a highly exergonic, irreversible transfer of a phosphate group to ADP catalyzed by pyruvate kinase.

18. 22.3 Glycolysis Overall Results of Glycolysis • Conversion of glucose to two pyruvate molecules. • Net production of two ATP molecules. • Production of two molecules of reduced coenzyme NADH from NAD+.

19. 22.4 Entry of Other Sugars into Glycolysis • Fructose is converted to glycolysis intermediates in two ways. • In muscle, it is phosphorylated to fructose 6-phosphate. • In the liver, it is converted to glyceraldehyde 3-phosphate. • Fructose 6-phosphate is the substrate for Step 3 of glycolysis; glyceraldehyde 3-phosphate is the substrate for Step 6.

20. 22.4 Entry of Other Sugars into Glycolysis • Galactose is converted to glucose 6-phosphate by a five-step pathway. • Mannose is a product of the hydrolysis of plant polysaccharides other than starch. It is converted by hexokinase and a multistep, enzyme-catalyzed rearrangement to fructose 6-phosphate as the substrate for Step 3.

21. 22.4 Entry of Other Sugars into Glycolysis Tooth Decay • The clinical term for tooth decay is dental caries. It is an infectious microbial disease that results in the destruction of the calcified structures of the teeth. • Dental plaque is defined as bacterial aggregations on the teeth that cannot be removed by a strong water spray. Plaque is not simply adherent food debris, but rather a community of microorganisms (known as a biofilm). • A diet high in sucrose favors the growth of S. mutans over that of S. sanguis. Although both bacteria can cause tooth decay, S. mutans attacks teeth much more vigorously. • Cleaning teeth by brushing and flossing disrupts the bacterial plaque, removing many of the bacteria. However, enough bacteria always remain so that the colonization process can begin anew almost immediately. • Many variables prevent or promote tooth decay, including the composition of saliva, the shape of the teeth, and exposure to fluoride.

22. 22.5 The Fate of Pyruvate • Under aerobic conditions, pyruvate is converted to acetyl-CoA. • Under anaerobic anaerobic conditions, pyruvate is instead reduced to lactate. • Yeast converts pyruvate to ethanol under anaerobic conditions.

23. 22.5 The Fate of Pyruvate Aerobic Oxidation of Pyruvate to Acetyl-CoA • Pyruvate moves across the outer mitochondrial membrane, then must be carried by a transporter protein across the inner mitochondrial membrane. • Once within the mitochondrial matrix, pyruvate encounters the pyruvate dehydrogenase complex, a large multienzyme complex that catalyzes the conversion of pyruvate to acetyl-CoA.

24. 22.5 The Fate of Pyruvate Anaerobic Reduction to Lactate • Under aerobic conditions, NADH is continually reoxidized during electron transport. • If electron transport slows down because of insufficient oxygen, NADH concentration increases and glycolysis cannot continue. • In reduction of pyruvate to lactate, NADH serves as the reducing agent and is reoxidized to NAD+.

25. 22.5 The Fate of Pyruvate Alcoholic Fermentation • Microorganisms have evolved numerous anaerobic strategies for energy production, generally known as fermentation. • When pyruvate undergoes fermentation by yeast, it is converted into ethanol plus carbon dioxide. This process, known as alcoholic fermentation, is used to produce beer, wine, and other alcoholic beverages and also to make bread. The carbon dioxide causes the bread to rise, and the alcohol evaporates during baking.

26. 22.6 Energy Output in Complete Catabolism of Glucose • The total energy output from oxidation of glucose is the combined result of • glycolysis, • the conversion of pyruvate to acetyl-CoA, • the conversion of two acetyl groups to four molecules of CO2 in the citric acid cycle, and • the passage of reduced coenzymes through electron transport and the production of ATP by oxidative phosphorylation.

27. 22.6 Energy Output in Complete Catabolism of Glucose

28. 22.6 Energy Output in Complete Catabolism of Glucose • 4 ATP molecules are produced per glucose molecule. • The remainder is generated via electron transport and oxidative phosphorylation. • Based on 3 ATP molecules per NADH and 2 ATP molecules per FADH2, the complete catabolism of one molecule of glucose produces 38 ATP molecules. • 38 ATP is most likely in bacteria and other prokaryotes. In humans the maximum is most likely 30–32 ATP.

29. 22.6 Energy Output in Complete Catabolism of Glucose Microbial Fermentations: Ancient and Modern • Residues in pottery in China and Egypt point to wine making as long as 9000 years ago. • Other microorganisms are important in producing cheese, sauerkraut, soy sauce, and other foods. • Any fruit can be fermented but many societies have focused on fermenting grapes. • Fermentation preserves some of the food value without spoilage. • Beer making from the fermentation of grain is nearly as old as wine production. • When curdled milk is fermented, cheese is produced. Fresh milk can also be fermented; we know these products as yogurt, sour cream, and buttermilk. • Not all bacterial fermentations are friendly. Clostridium species are responsible for gas gangrene

30. 22.7 Regulation of Glucose Metabolism and Energy Production • Normal blood glucose concentration ranges from 65 to 100 mg/dL. • Hypoglycemia causes weakness, sweating, and rapid heartbeat, and in severe cases, low glucose in brain cells causes mental confusion, convulsions, coma, and eventually death. • Hyperglycemia causes increased urine flow as the normal osmolarity balance of fluids within the kidney is disturbed. Prolonged hyperglycemia can cause low blood pressure, coma, and death.

31. 22.7 Regulation of Glucose Metabolism and Energy Production • Insulin is released when blood glucose concentration rises. Its role is to accelerate the uptake of glucose by cells. • Glucagon is released when blood glucose concentration drops. Glucagon stimulates the breakdown of glycogen in the liver and release of glucose.

32. 22.8 Metabolism in Fasting and Starvation • In the absence of food, a gradual decline in blood glucose concentration is accompanied by an increased release of glucose from glycogen. • As glucose and glycogen reserves are exhausted, metabolism turns to breakdown of proteins. Protein is used at a rate as high as 75 g/day. • Lipid catabolism is mobilized, and acetyl-CoA molecules derived from breakdown of lipids accumulate.

33. 22.8 Metabolism in Fasting and Starvation • Acetyl-CoA is converted to ketone bodies. • The brain and other tissues are able to switch over to producing up to 50% of their ATP from catabolism of ketone bodies instead of glucose. • By the fortieth day of starvation, metabolism has stabilized at the use of about 25 g of protein and 180 g of fat each day. • With adequate water, an average person can survive in this state for several months; those with more fat can survive longer.

34. 22.9 Metabolism in Diabetes Mellitus • Diabetes mellitus is one of the most common metabolic diseases. • Type I or juvenile-onset diabetes is caused by failure of the pancreatic cells to produce enough insulin. • In Type II or adult-onset diabetes, insulin is in good supply but fails to promote the passage of glucose across cell membranes. • Recently identified is a pre-diabetic condition called metabolic syndrome.

35. 22.9 Metabolism in Diabetes Mellitus • The symptoms of diabetes (Type I) are: • Excessive thirst accompanied by frequent urination, • Abnormally high glucose concentrations in urine and blood, • Wasting of the body despite a good diet. • Available glucose does not enter cells where it is needed, and spills over into the urine. • In untreated diabetes, metabolism proceeds through the same stages as in starvation. • Type I or juvenile-onset diabetes is caused by failure of the pancreatic cells to produce enough insulin.

36. 22.9 Metabolism in Diabetes Mellitus • Type II diabetes results when cell membrane receptors fail to recognize insulin. This state is sometimes referred to as insulin resistance. • Drugs that increase insulin or insulin receptor levels are effective, as are diet modification and exercise. • Metabolic syndrome has elevated fasting blood glucose levels and impaired glucose response. • It is characterized by abdominal obesity, elevated blood pressure and impaired glucose metabolism. Treatment involves changes in diet and exercise.

37. 22.9 Metabolism in Diabetes Mellitus • Type I diabetes is classified as an autoimmune disease. • The immune system identifies pancreatic beta cells as foreign, develops antibodies to them, and destroys them. • To treat Type I diabetes, the missing insulin must be supplied by injection. • Individuals with diabetes are subject to cataracts, blood vessel lesions and gangrene in the legs.

38. 22.9 Metabolism in Diabetes Mellitus • Ketoacidosis results from the buildup of acidic ketones in the late stages of uncontrolled diabetes. • This condition can lead to coma and diminished brain function, but can be reversed by timely insulin administration. • Hypoglycemia, or “insulin shock,” by contrast, may be due to an overdose of insulin or failure to eat. • If untreated, diabetic hypoglycemia can cause nerve damage or death.

39. 22.9 Metabolism in Diabetes Mellitus Diagnosis and Monitoring of Diabetes Key diagnostic features: • Frequent urination, excessive thirst, rapid weight loss (Type I only). • Random blood glucose concentration (without fasting) greater than 200 mg/dL. • Fasting blood glucose greater than 140 mg/dL • Sustained blood glucose concentration greater than 200 mg/dL after glucose challenge in glucose tolerance test. • Individuals with diabetes must monitor their blood glucose levels at home daily, often several times a day. • Most tests for glucose in urine or blood rely on detecting a color change that accompanies the oxidation of glucose. • The blood test is desirable because it is more specific and it detects rising glucose levels earlier than the urine test.

40. 22.10 Glycogen Metabolism: Glycogenesis and Glycogenolysis • Glycogen synthesis, known as glycogenesis, occurs when glucose concentrations are high. It begins with glucose 6-phosphate.

41. 22.10 Glycogen Metabolism: Glycogenesis and Glycogenolysis • Glucose 6-phosphate is isomerized to glucose 1-phosphate by phosphoglucomutase. • Glucose residue is then attached to uridine diphosphate (UDP). • The diphosphate is then hydrolyzed, yielding two hydrogen phosphate ions. • The resulting glucose-UDP transfers glucose to a growing glycogen chain in an exergonic reaction catalyzed by glycogen synthase.

42. 22.10 Glycogen Metabolism: Glycogenesis and Glycogenolysis • Glycogenolysis occurs in two steps. • Glucose 1-phosphate is formed by the action of glycogen phosphorylase on a terminal glucose residue in glycogen. • Glucose 1-phosphate is then converted to glucose 6-phosphate by phosphoglucomutase. • In muscle cells, glycogenolysis occurs when there is an immediate need for energy. • Because glucose 6-phosphate cannot cross cell membranes, liver cells contain glucose 6-phosphatase, an enzyme that hydrolyzes glucose 6-phosphate to free glucose.

43. 22.10 Glycogen Metabolism: Glycogenesis and Glycogenolysis The Biochemistry of Running • Levels of epinephrine have readied the body for action. Chemical reactions in muscle cells will provide the energy to see the race through. • The supply of immediately available ATP, but this is used up within a matter of seconds. • Additional ATP is provided by the reaction of ADP with creatine phosphate, an amino acid phosphate in muscle cells. • After 30 seconds to a minute, stores of creatine phosphate are depleted, and glucose from glycogenolysis becomes the chief energy source. • During maximum muscle exertion, oxygen cannot enter muscle cells fast enough to keep the citric acid cycle and oxidative phosphorylation going. • Pyruvate from glycolysis is converted to lactate rather than entering the citric acid cycle. • The trick to avoiding muscle exhaustion in a long race is to run at a speed just under the “anaerobic threshold”—the rate of exertion at which oxygen is in short supply.

44. 22.11 Gluconeogenesis: Glucose from Noncarbohydrates • Lactate is a product of glycolysis in red blood cells and in muscle cells during vigorous muscle activity. • Lactate absorbed from the blood is converted to pyruvate, the reactant for the first step of gluconeogenesis. • The new glucose synthesized in the liver is then returned to the muscles. • The Cori cycle, is named for Carl and Gerti Cori who won the Nobel Prize in Medicine in 1947 for their work on glycogen metabolism.

45. 22.11 Gluconeogenesis: Glucose from Noncarbohydrates • Gluconeogenesis begins in mitochondria with conversion of pyruvate to phosphoenolpyruvate. • Pyruvate formed from lactate is transported from the cytosol into the mitochondria or is produced there from amino acids. • In Step 1 of gluconeogenesis, pyruvate is converted to oxaloacetate by pyruvate carboxylase in an energy-expensive reaction that bypasses the last, irreversible step in glycolysis. • Next, oxaloacetate is reduced to malate, transported into the cytosol and reconverted to oxaloacetate.

46. 22.11 Gluconeogenesis: Glucose from Noncarbohydrates • In Step 2, phosphoenolpyruvate carboxykinase adds a phosphate group and rearranges oxaloacetate to produce phosphoenolpyruvate. This is the first of three instances that bypass irreversible steps in glycolysis. • The next five reactions of the 10-step glycolysis pathway are reversible. They occur in reverse, catalyzed by the same enzymes as in glycolysis. • Step 8 is the conversion of fructose 1,6 bisphosphate to fructose 6-phosphate. Fructose 1,6-bisphosphatase removes a phosphate group by hydrolysis in an energetically favorable reaction.

47. 22.11 Gluconeogenesis: Glucose from Noncarbohydrates • The next to last reaction converts of fructose 6-phosphate to glucose 6-phosphate. • The final reaction in the pathway is the third bypass of a glycolysis pathway reaction. Glucose 6-phosphatase hydrolyzes glucose 6-phosphate producing glucose and inorganic phosphate. The glucose produced crosses the cell membrane and is transported to cells that use only glucose for energy generation. • Glycerol is converted to dihydroxyacetone phosphate and enters the gluconeogenesis pathway at Step 7. • The carbon atoms from certain amino acids enter gluconeogenesis as either pyruvate or oxaloacetate.

48. 22.11 Gluconeogenesis: Glucose from Noncarbohydrates • The pathway begins at the bottom and moves upwards. Enzymes shaded in blue differ from the enzymes used in glycolysis. For the other steps, gluconeogenesis uses the same enzymes as those used in glycolysis.

49. Chapter Summary • What happens during digestion of carbohydrates? Carbohydrate digestion, the hydrolysis of disaccharides and polysaccharides, begins in the mouth and continues in the stomach and small intestine. The products that enter the bloodstream from the small intestine are monosaccharides—mainly glucose, fructose, and galactose. • What are the major pathways in the metabolism of glucose? The major pathway for glucose, once inside a cell and converted to glucose 6-phosphate, is glycolysis. Pyruvate, the end product of glycolysis, is then fed into the citric acid cycle via acetyl-CoA. One alternative pathway for glucose is glycogenesis, the synthesis of glycogen, which is stored mainly in the liver and muscles. Another alternative is the pentose phosphate pathway, which provides the 5-carbon sugars and NADPH needed for biosynthesis.

50. Chapter Summary, Continued • What is glycolysis? • Glycolysis is a 10-step pathway that produces two molecules of pyruvate, two molecules of reduced coenzyme (NADH), and two ATP molecules for each molecule of glucose metabolized. • Glycolysis begins with phosphorylation to form fructose 1,6-bisphosphate, followed by cleavage and isomerization reactions that produce two molecules of glyceraldehyde 3-phosphate. • Each glyceraldehyde 3-phosphate then proceeds through the energy-generating steps in which phosphates are alternately created and then donate their phosphate groups to ADP to yield ATP. • Dietary monosaccharides other than glucose enter glycolysis at various points—fructose as fructose 6-phosphate or glyceraldehyde 3-phosphate, galactose as glucose 6-phosphate, and mannose as fructose 6-phosphate.