Chapter Twenty Three

1. Chapter Twenty Three Carbohydrate Metabolism

2. Outline • 23.1 Digestion of Carbohydrates • 23.2 Glucose Metabolism: An Overview • 23.3 Glycolysis • 23.4 Entry of Other Sugars into Glycolysis • 23.5 The Fate of Pyruvate • 23.6 Energy Output in Complete Catabolism of Glucose • 23.7 Regulation of Glucose Metabolism and Energy Production • 23.8 Metabolism in Fasting and Starvation • 23.9 Metabolism in Diabetes Mellitus • 23.10 Glycogen Metabolism: Glycogenesis and Glycogenolysis • 23.11 Gluconeogenesis: Glucose from Noncarbohydrates Chapter Twenty Three

3. 23.1 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, a-amylase in saliva catalyzes hydrolysis of the glycosidic bonds in carbohydrates. Salivary a-amylase continues to act on polysaccharides in the stomach until, after an hour or so, it is inactivated by stomach acid. No further carbohydrate digestion takes place in the stomach. Chapter Twenty Three

4. a-Amylase is secreted by the pancreas and enters the small intestine, where conversion of polysaccharides to maltose continues. • Enzymes from the mucous lining of the small intestine hydrolyze maltose, sucrose and lactose to glucose, fructose, and galactose, which are then transported across the intestinal wall into the bloodstream. Chapter Twenty Three

5. 23.2 Glucose Metabolism: An Overview • When glucose enters a cell from the bloodstream, it is immediately converted to glucose 6-phosphate. • Once this phosphate is formed, glucose is trapped within the cell because phosphorylated molecules cannot cross the cell membrane. • Like the first step in many metabolic pathways, the formation of glucose-6-phosphate is highly exergonic and not reversible in the glycolytic pathway, thereby committing the initial substrate to subsequent reactions. Chapter Twenty Three

6. Glucose-6-phosphate can enter the pentose phosphate pathway. This multistep pathway yields two products of importance to our metabolism. • One is a supply of the coenzyme NADPH, a reducing agent that is essential for various biochemical reactions. • The other is ribose 5-phosphate, which is necessary for the synthesis of nucleic acids (DNA and RNA). • Glucose-6-phosphate enters the pentose phosphate pathway when a cell’s need for NADPH or ribose-5-phosphate exceeds its need for ATP. Chapter Twenty Three

7. When cells are already well supplied with glucose, the excess glucose is converted to other forms for storage: to glycogen, the glucose storage polymer, by the glycogenesis pathway, or to fatty acids by entrance of acetyl-SCoA into the pathways of lipid metabolism rather than the citric acid cycle. • When energy is needed, glucose 6-phosphate undergoes glycolysis to pyruvate and then to acetyl-S-coenzyme A, which enters the citric acid cycle. Chapter Twenty Three

8. Glucose 6-phosphate can be converted to pentose products, stored as glycogen, or broken down to acetyl-SCoA for production of energy, proteins, or fats. Chapter Twenty Three

9. 23.3 Glycolysis • Glycolysis is a series of 10 enzyme-catalyzed reactions that break down glucose molecules. • The net result of glycolysis is the production of two pyruvate molecules, two ATPs, and two NADH/H+s. Chapter Twenty Three

10. Steps 1-5 of glycolysis break one glucose molecule down into two D-glyceraldehyde 3-phosphate fragments. • An investment of 2 ATP molecules is required. Chapter Twenty Three

11. Steps 6-10 occur twice for each glucose that enters in at step 1. • Steps 6-10 produce: 2 pyruvates, 4 ATPs 2 NADH/H+ per glucose. Chapter Twenty Three

12. 23.4 Entry of Other Sugars into Glycolysis • The major monosaccharides from digestion other than glucose also eventually join the glycolysis pathway. • Fructose, from fruits or hydrolysis of the disaccharide sucrose, 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. Chapter Twenty Three

13. Mannoseis a product of the hydrolysis of plant polysaccharides other than starch. Chapter Twenty Three

14. Mannose is converted by hexokinase to a 6-phosphate, which then undergoes a multistep, enzyme-catalyzed rearrangement and enters glycolysis as fructose 6-phosphate. • Galactose from hydrolysis of the disaccharide lactose is converted to glucose 6- phosphate by a five-step pathway. • A hereditary defect affecting any enzyme in this pathway can be a cause of galactosemia. Chapter Twenty Three

15. 23.5 The Fate of Pyruvate • The conversion of glucose to pyruvate is a central metabolic pathway in most living systems. • The further reactions of pyruvate depend on metabolic conditions and on the nature of the organism. Chapter Twenty Three

16. Aerobic: In the presence of oxygen. • Under normal oxygen-rich (aerobic) conditions, pyruvate is converted to acetyl-SCoA. • Pyruvate diffuses across the outer mitochondrial membrane, then is carried by a transporter protein across the inner mitochondrial membrane. • Once inside, pyruvate dehydrogenase complex catalyzes the conversion of pyruvate to acetyl-SCoA. Chapter Twenty Three

17. Anaerobic: In the absence of oxygen. • If electron transport slows because of insufficient oxygen, NADH concentration increases, NAD+ is in short supply, and glycolysis cannot continue. • An alternative way to reoxidize NADH is essential because glycolysis, the only available source of fresh ATP, mustcontinue. The reduction of pyruvate to lactate solves the problem. Chapter Twenty Three

18. NADH serves as the reducing agent and is reoxidized to NAD+ which is then available in the cytosol for glycolysis. Lactate formation serves no purpose other than NAD+ production, and the lactate is reoxidized to pyruvate when oxygen is available. • Microorganisms often must survive in the absence of oxygen and 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. Chapter Twenty Three

19. 23.6 Energy Output in Complete Catabolism of Glucose • The total energy output from oxidation of glucose is the combined result of • (a) glycolysis • (b) conversion of pyruvate to acetyl-SCoA • (c) conversion of two acetyl groups to four molecules of CO2 in the citric acid cycle • (d) the passage of reduced coenzymes from each of these pathways through electron transport and the production of ATP by oxidative phosphorylation. Chapter Twenty Three

20. The sum of the net equations for each pathway that precedes oxidative phosphorylation is shown below. • Since each glucose yields 2 pyruvates and 2 acetyl-SCoAs, the net equations for pyruvate oxidation and the citric acid cycle are multiplied by 2. Chapter Twenty Three

21. The total number of ATPs per glucose molecule is the 4 ATPs from glucose catabolism plus the number of ATPs produced for each reduced coenzyme that enters electron transport. • For a long time, based on the belief that 3 ATPs are generated per NADH and 2 ATPs per FADH2 the maximum yield was taken as 38 ATPs. • 10 NADH(3ATP/NADH) + 2 FADH2(2ATP/FADH2) + 4 ATP = 38 ATP • The 38 ATPs per glucose molecule are viewed as a maximum yield of ATP, most likely possible in bacteria and other prokaryotes. In humans and other mammals, the maximum is most likely 30–32 ATPs per glucose molecule. Chapter Twenty Three

22. 23.7 Regulation of Glucose Metabolism and Energy Production • Normal blood glucose concentration a few hours after a meal ranges roughly from 65 to 110 mg/dL. • Hypoglycemia: Lower-than normal blood glucose concentration. • Hyperglycemia: Higher-than normal blood glucose concentration. Chapter Twenty Three

23. Low blood glucose (hypoglycemia) causes weakness, sweating, and rapid heartbeat, and in severe cases, low glucose in brain cells causes mental confusion, convulsions, coma, and eventually death. The brain can use onlyglucose as a source of energy. At a blood glucose level of 30 mg/dL, consciousness is impaired or lost, and prolonged hypoglycemia can cause permanent dementia. • High blood glucose (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. Chapter Twenty Three

24. Two hormones from the pancreas have the major responsibility for blood glucose regulation. • The first, insulin, is released when blood glucose concentration rises. • The second hormone, glucagon, is released when blood glucose concentration drops. Chapter Twenty Three

25. 23.8 Metabolism in Fasting and Starvation • The metabolic changes in the absence of food begin with a gradual decline in blood glucose concentration accompanied by an increased release of glucose from glycogen. • All cells contain glycogen, but most is stored in liver cells (about 90 g in a 70-kg man) and muscle cells (about 350 g in a 70-kg man). Free glucose and glycogen represent less than 1% of our energy reserves and are used up in 15–20 hours of normal activity (3 hours in a marathon race). Chapter Twenty Three

26. During the first few days of starvation, protein is used up at a rate as high as 75 g/day. • Lipid catabolism is mobilized, and acetyl-SCoA molecules derived from breakdown of lipids accumulate. • Acetyl-SCoA begins to be removed by a new series of metabolic reactions that transform it into ketone bodies. Chapter Twenty Three

27. As starvation continues, the brain and other tissues are able to switch over to producing up to 50% of their ATP from catabolizing ketone bodies instead of glucose. By the 40th day of starvation, metabolism has stabilized at the use of about 25 g of protein and 180 g of fat each day. So long as adequate water is available, an average person can survive in this state for several months; those with more fat can survive longer. Chapter Twenty Three

28. 23.9 Metabolism in Diabetes Mellitus • Diabetes mellitus: A chronic condition due to either insufficient insulin or failure of insulin to activate crossing of cell membranes, by glucose. • The symptoms by which diabetes is usually detected are excessive thirst accompanied by frequent urination, abnormally high glucose concentrations in urine and blood, and wasting of the body despite a good diet. These symptoms result when available glucose does not enter cells where it is needed. Chapter Twenty Three

29. Type II diabetes is thought to result when cell membrane receptors fail to recognize insulin. Drugs that increase either insulin or insulin receptor levels are an effective treatment because more of the undamaged receptors are put to work. • Type I diabetes is classified as an autoimmune disease, a condition in which the body misidentifies some part of itself as an invader. Gradually, the immune system wrongly identifies pancreatic beta cells as foreign matter, develops antibodies to them, and destroys them. To treat Type I diabetes, the missing insulin must be supplied by injection. Chapter Twenty Three

30. Diabetic individuals are subject to several serious conditions that result from elevated blood glucose levels. Excess glucose is reduced to sorbitol. • Sorbitol is not transported out of the cell. Its rising concentration increases the osmolarity of fluid in the eye, causing increased pressure, cataracts, and blindness. Elevated sorbitol is also associated with blood vessel lesions and gangrene in the legs. • Ketoacidosis results from the buildup of acidic ketones in the late stages of uncontrolled diabetes. It can lead to coma and diminished brain function. • Hypoglycemia by contrast, may be due to an overdose of insulin or failure to eat. Diabetic hypoglycemia can cause nerve damage or death. Chapter Twenty Three

31. 23.10 Glycogen Metabolism: Glycogenesis and Glycogenolysis • Glycogen synthesis, known as glycogenesis, occurs when glucose concentrations are high. • Glucose 6-phosphate is first isomerized to glucose 1-phosphate. • The glucose residue is then attached to uridine diphosphate (UDP): Chapter Twenty Three

32. The resulting glucose-UDP transfers glucose to a growing glycogen chain in an exergonic reaction. Chapter Twenty Three

33. Glycogenolysis: The biochemical pathway for breakdown of glycogen to free glucose. • Glycogenolysis occurs in muscle cellswhen there is an immediate need for energy. • Glycogenolysis occurs in the liver when blood glucose is low. Chapter Twenty Three

34. 23.11 Gluconeogenesis: Glucose from Noncarbohydrates • Gluconeogenesis, which occurs mainly in the liver, is the pathway for making glucose from noncarbohydrate molecules—lactate, amino acids, and glycerol. • This pathway becomes critical during fasting and the early stages of starvation. Failure of gluconeogenesis is usually fatal. • During exercise lactate produced in muscles under anaerobic conditions during exercise is sent to the liver, where it is converted back to glucose. Chapter Twenty Three

35. Gluconeogenesis requires energy, so shifting this pathway to the liver frees the muscles from the burden of having to produce even more energy. Chapter Twenty Three

36. Steps 1, 3, and 10 in glycolysis are too exergonic to be directly reversed. Gluconeogenesis uses reactions catalyzed by different enzymes that reverse these steps. The 7 other steps of glycolysis are reversible because they operate at near-equilibrium conditions. • Gluconeogenesis begins with conversion of pyruvate to phosphoenolpyruvate, the reverse of the highly exergonic step 10 of glycolysis. Two steps are required, utilizing two enzymes and the energy provided by two triphosphates, ATP and GTP. Chapter Twenty Three

37. Chapter Summary • 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. • Glucose is converted to glucose 6-phosphate and undergoes glycolysis to pyruvate, which is fed into the citric acid cycle via acetyl-SCoA. One alternative pathway for glucose is glycogenesis, the synthesis of glycogen. Another is the pentose phosphate pathway, which provides the five-carbon sugars and NADPH needed for biosynthesis. Chapter Twenty Three

38. Chapter Summary Cont. • Glycolysis is a 10-step pathway that produces two molecules of pyruvate, two reduced coenzymes (NADH), and two ATPs for each molecule of glucose metabolized. • When oxygen is in good supply, pyruvate is transported into mitochondria and converted to acetyl-SCoA for energy generation via the citric acid cycle and oxidative phosphorylation. • When there is insufficient oxygen, pyruvate is reduced to L-lactate, with the production of the oxidized coenzyme NAD+ that is essential to the continuation of glycolysis. • In the presence of yeast, pyruvate undergoes anaerobic fermentationto yield ethyl alcohol. Chapter Twenty Three

39. Chapter Summary Cont. • Insulin, produced when blood glucose concentration rises, accelerates glycolysis and glycogen synthesis. Glucagon, produced when blood glucose concentration drops, accelerates production of glucose in the liver from stored glycogen and from other precursors via the gluconeogenesis pathway. • Adaptation to starvation begins with the effects of glucagon and energy production from protein, and then proceeds to reliance on ketone bodies from fatty tissue for energy generation. • Diabetes mellitus may be insulin-dependent or non-insulin-dependent. Among the serious outcomes of uncontrolled diabetes are cataracts, blood vessel lesions, ketoacidosis, and hypoglycemia. Chapter Twenty Three

40. Chapter Summary Cont. • Glycogenesis, the synthesis of the polysaccharide glycogen, puts excess glucose into storage, mainly in muscles and the liver. • Glycogenolysis is the release of stored glucose from glycogen. Glycogenolysis occurs in muscles when there is an immediate need for energy. It occurs in the liver when blood glucose concentration is low. • Gluconeogenesis maintains glucose levels by synthesizing it from lactate, from certain amino acids derived from proteins, and from glycerol derived from fatty tissue; it is critical during fasting and starvation. Chapter Twenty Three

41. End of Chapter 23 Chapter Twenty Three