1. Prentice Hall c2002Chapter 131 Chapter 13 Additional Pathways in Carbohydrate Metabolism Insulin, a 51 amino acid polypeptide that regulates carbohydrate and lipid metabolism

2. Prentice Hall c2002Chapter 132 Glycogen Degradation Glucose is stored in mammals as glycogen Glycogen is stored in cytosolic granules in muscle and liver cells Glycogenolysis - degradation of glycogen Glycogen breakdown yields glucose 1-phosphate which can be converted to glucose 6-phosphate for metabolism by glycolysis and the citric acid cycle

3. Prentice Hall c2002Chapter 133 Glycogen particles in a liver cell section

4. Prentice Hall c2002Chapter 134 The enzyme Glycogen Phosphorylase Catalyzes phosphorolysis - cleavage of a bond by group transfer to an oxygen atom of phosphate Glycogen Phosphorylase removes glucose residues from the ends of glycogen Acts only on  -1-4 linkages of a glycogen polymer The product is glucose 1-phosphate, which is converted to glucose 6-phosphate

5. Prentice Hall c2002Chapter 135 Fig 13.1 Cleavage of a glucose residue from the end of glycogen

6. Prentice Hall c2002Chapter 136 Degradation of Glycogen by Glycogen Phosphorylase Glycogen phosphorylase catalyzes the sequential removal of glucose residues from the ends of glycogen Stops 4 glucose residues from an  1-6 branch point Resulting limit dextrin is further degraded by a glycogen- debranching enzyme, producing a free glucose molecule and an elongated unbranched chain

7. Prentice Hall c2002Chapter 137 Fig 13.3

8. Prentice Hall c2002Chapter 138 Metabolism of Glucose 1-Phosphate Phosphoglucomutase catalyzes the conversion of glucose 1-phosphate to glucose 6-phosphate

9. Prentice Hall c2002Chapter 139 Glycogen Synthesis Glycogen is synthesized from excess glucose for storage Synthesis and degradation of glycogen require separate enzymatic steps Cellular glucose is converted to glucose 6-phosphate by the enzyme hexokinase Three separate enzymatic steps are required to incorporate one glucose 6-phosphate into glycogen Glycogen synthase catalyzes the major regulatory step

10. Prentice Hall c2002Chapter 1310 Fig 13.4 Synthesis of glycogen from glucose 6-phosphate

11. Prentice Hall c2002Chapter 1311 Fig. 13.5 Glycogen synthase adds glucose to the end of a glycogen chain

12. Prentice Hall c2002Chapter 1312 Regulation of Glycogen Metabolism Muscle glycogen is fuel for muscle contraction Liver glycogen is mostly converted to glucose for bloodstream transport to other tissues Both mobilization and synthesis of glycogen are regulated by hormones Insulin, glucagon and epinephrine are hormones that regulate glycogen metabolism

13. Prentice Hall c2002Chapter 1313 Hormones Regulate Glycogen Metabolism Insulin is produced by  -cells of the pancreas in response to high blood glucose Insulin increases the rate of glucose transport into muscle and adipose tissue via the glucose transporter (GLUT 4) Glucagon is secreted by the  cells of the pancreas in response to low blood glucose Glucagon stimulates glycogen degradation to restore blood glucose to steady-state levels Epinephrine (adrenaline) is released from the adrenal glands in response to sudden energy requirement (“fight or flight”) Epinephrine stimulates the breakdown of glycogen to glucose 1- phosphate

14. Prentice Hall c2002Chapter 1314 Fig 13.6 Effects of hormones on glycogen metabolism

15. Prentice Hall c2002Chapter 1315 Reciprocal Regulation of Glycogen Phosphorylase and Glycogen Synthase Glycogen phosphorylase and glycogen synthase are reciprocally regulated. When one is active the other is inactive. Covalent regulation by phosphorylation (-P) and dephosphorylation (-OH) and allosteric regulation. Active form “a”Inactive form “b” Glycogen phosphorylase -P -OH Glycogen synthase -OH -P GP a (active form) - inhibited by glucose 6-phosphate GS b (inactive form) - activated by glucose 6-phosphate

16. Prentice Hall c2002Chapter 1316 Gluconeogenesis Liver and kidney can synthesize glucose from noncarbohydrate precursors such as lactate and alanine Under fasting conditions, gluconeogenesis supplies almost all of the body’s glucose 2 Pyruvate + 2 NADH + 4 ATP + 2 GTP + 6 H 2 O + 2 H + Glucose + 2 NAD + + 4 ADP + 2 GDP + 6 P i

17. Prentice Hall c2002Chapter 1317 Fig. 13.10 Comparison of gluconeogenesis and glycolysis

18. Prentice Hall c2002Chapter 1318 Fig 13.10

19. Prentice Hall c2002Chapter 1319 Pyruvate carboxylase Catalyzes a metabolically irreversible reaction Allosterically activated by acetyl CoA Accumulation of acetyl CoA signals abundant energy, and directs pyruvate to oxaloacetate for gluconeogenesis

20. Prentice Hall c2002Chapter 1320 Phosphoenolpyruvate carboxykinase (PEPCK) A decarboxylation reaction in which GTP donates a phosphoryl group

21. Prentice Hall c2002Chapter 1321 Fructose 1,6-bisphosphatase (F1,6BPase) Catalyzes a metabolically irreversible reaction F1,6BPase is allosterically inhibited by AMP and fructose 2,6-bisphosphate (F2,6BP)

22. Prentice Hall c2002Chapter 1322 Glucose 6-phosphatase Catalyzes a metabolically irreversible hydrolysis reaction

23. Prentice Hall c2002Chapter 1323 Precursors for Gluconeogenesis Any metabolite that can be converted to pyruvate or oxaloacetate can be a glucose precursor Major gluconeogenic precursors in mammals: (1) Lactate (2) Most amino acids (especially alanine), (3) Glycerol (from triacylglycerol hydrolysis)

24. Prentice Hall c2002Chapter 1324 Lactate Glycolysis generates large amounts of lactate in active muscle Liver lactate dehydrogenase converts lactate to pyruvate (a substrate for gluconeogensis) Glucose produced by liver is delivered to peripheral tissues via the bloodstream Fig 13.12 The Cori Cycle The interaction of glycolysis and gluconeogenesis

25. Prentice Hall c2002Chapter 1325 Amino Acids Carbon skeletons of most amino acids are catabolized to pyruvate or citric acid cycle intermediates The glucose-alanine cycle: (1) Transamination of pyruvate yields alanine which travels to the liver (2) Transamination of alanine in the liver yields pyruvate for gluconeogenesis (3) Glucose is released to the bloodstream

26. Prentice Hall c2002Chapter 1326 Gluconeogensis from Glycerol

27. Prentice Hall c2002Chapter 1327 Regulation of Gluconeogenesis Substrate cycle - two opposing enzymes: (1) Phosphofructokinase-1 (glycolysis) (2) Fructose 1,6-bisphosphatase (gluconeogenesis) Modulating one enzyme in a substrate cycle will alter the flux through the two opposing pathways Inhibiting Phosphofructokinase-1 stimulates gluconeogenesis Inhibiting Fructose 1,6-bisphosphatase stimulates glycolysis

28. Prentice Hall c2002Chapter 1328 Regulation of liver glycolysis and gluconeogenesis

29. Prentice Hall c2002Chapter 1329 The Pentose Phosphate Pathway Glucose can enter this pathway after conversion to glucose 6-phosphate Pathway has two primary products: (1) NADPH (for reductive biosynthesis) (2) Ribose 5-phosphate (R5P) for the biosynthesis of ribonucleotides (RNA, DNA)

30. Prentice Hall c2002Chapter 1330 Maintenance of Glucose Levels in Mammals Glucose is the major metabolic fuel in the body Mammals maintain blood glucose levels within strict limits (~3mM to 10mM) High levels of blood glucose are filtered out by the kidneys The brain relies almost solely on glucose for energy needs The liver participates in the interconversions of all types of metabolic fuels: carbohydrates, amino acids and fatty acids Products of digestion pass immediately to the liver for metabolism or redistribution The liver regulates distribution of dietary fuels and supplies fuel from its own reserves

31. Prentice Hall c2002Chapter 1331 Fig 13.23 Placement of the liver in circulation

32. Prentice Hall c2002Chapter 1332 Fig 13.24 Five phases of glucose homeostasis Graph illustrates glucose utilization after 100g glucose consumption then 40 day fast Fatty acid breakdown Protein breakdown

33. Prentice Hall c2002Chapter 1333 Entry into starvation Fuel reserves of a human are: Glycogen in the liver and muscle Triacylglycerols in adipose tissue Tissue Proteins After an overnight fast glycogen is essentially used up. Within 24 hours blood glucose concentration falls. Insulin secretion slows down, glucagon is increased. Triacylglycerols are broken down as fuel for muscle and liver. The brain needs glucose. Proteins are degraded and their carbon skeletons used for gluconeogenesis. The amino groups are excreted as urea.

34. Prentice Hall c2002Chapter 1334 How much energy is stored in our bodies? How long will it last?