1. Carbohydrate Metabolism

2. Chapter 8 Carbohydrate Metabolism Overview Metabolism
Section 8.1: Glycolysis
Section 8.2: Gluconeogenesis
Section 8.3: The Pentose Phosphate Pathway
Section 8.4: Metabolism of Other Important Sugars
Section 8.5: Glycogen Metabolism
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

3. Metabolism and Jet Engines
Carbohydrate Metabolism: Biochemical processes responsible for the formation, breakdown and interconversion of carbohydrates in living organisms
Energy transforming pathways of carbohydrate metabolism include: glycolysis,
Glycogenesis
Glycogenolysis
Gluconeogenesis
pentose phosphate pathway
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

4. Glycolysis occurs in almost every living cell
Section 8.1: Glycolysis
Figure 8.2 Major Pathways in Carbohydrate Metabolism
Glycolysis occurs in almost every living cell
Ancient process central to all life
Splits glucose into two three-carbon pyruvate units
Catabolic process that captures some energy as 2 ATP and 2 NADH
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

5. ATP
Adenosine triphosphate (ATP) is a nucleoside triphosphate used in cells as a coenzyme to store and transport chemical energy

7. NAD+/NADH
Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells that transfers electrons between reactions in metabolism.

8. Nicotinamide adenine dinucleotide phosphate
NADPH is the reduced form of NADP+.
NADP+ differs from NAD+ in the presence of an additional phosphate group on the 2' position of the ribose ring that carries the adenine moiety.
NADPH is a cofactor used in anabolic reactions, such as lipid and nucleic acid synthesis, which require NADPH as a reducing agent.

9. Glycolysis is an anaerobic process

10. Pyruvate The conjugate base of pyruvic acid
It is a key intermediate in several metabolic pathways
Made from glucose through glycolysis
Converted back to carbohydrates (such as glucose) via gluconeogenesis, or to fatty acids through acetyl-CoA.
Used to construct the amino acid alanine, and be converted into ethanol or lactic acid via fermentation.
Pyruvic Acid
Alanine

11. Section 8.1: Glycolysis The Fates of Pyruvate
Figure 8.7 The Fates of Pyruvate
The Fates of Pyruvate
Under aerobic conditions, pyruvate is converted to acetyl-CoA for use in the citric acid cycle and electron transport chain
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

12. Section 8.1: Glycolysis The Fates of Pyruvate
Figure 8.7 The Fates of Pyruvate
The Fates of Pyruvate
Under anaerobic conditions pyruvate can undergo fermentation: alcoholic or homolactic
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

13. Section 8.1: Glycolysis Energetics of Glycolysis
Figure 8.9 Free Energy Changes during Glycolysis in Red Blood Cells
Energetics of Glycolysis
In red blood cells, only three reactions have significantly negative DG values
Many reactions are reversible
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

14. Regulation of Glycolysis
Section 8.1: Glycolysis
Regulation of Glycolysis
The rate of the glycolytic pathway in a cell is controlled by the allosteric enzymes:
Hexokinases I, II, and III
Phosphofructokinase 1 (PFK-1)
Pyruvate kinase
Reactions catalyzed by these allosteric enzymes can be turned on or off by activator or inhibitor molecules
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

15. Regulation of Glycolysis Continued
Section 8.1: Glycolysis
Regulation of Glycolysis Continued
Pyruvate kinase (converts PEP to pyruvate) activated by high AMP concentrations, inhibited ATP
PFK-1 is activated by fructose-2,6-bisphosphate, produced via hormone- induced covalent modification of PFK-2
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

16. Section 8.1: Glycolysis
The peptide hormones glucagon and insulin also regulate glycolysis/gluconeogenesis pathways
Glucagon is released by pancreatic alpha-cells when blood glucose is low; triggers a series of reactions that inhibit glycolysis and activate gluconeogenesis
Insulin is released by pancreatic beta-cells when blood glucose is high; triggers a series of reactions that activate glycolysis and inhibit gluconeogenesis
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

17. Section 8.2: Gluconeogenesis
Gluconeogenesis is the formation of new glucose molecules from precursors in the liver
Occurs when blood sugar levels are low and liver glycogen is depleted
Precursor molecules include lactate, pyruvate, and a-keto acids
Gluconeogenesis Reactions
Reverse of glycolysis except the three irreversible reactions
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

18. 3 2 1 Gluconeogenesis Reactions Three bypass reactions:
1. Synthesis of phosphoenolpyruvate (PEP) via the enzymes pyruvate carboxylase and pyruvate carboxykinase
2. Conversion of fructose-1,6-bisphosphate to fructose-6-phosphate via the enzyme fructose-1,6-bisphosphatase
3. Formation of glucose from glucose-6-phosphate via the liver and kidney-specific enzyme glucose-6-phosphatase 2 1

19. Section 8.2: Gluconeogenesis
Gluconeogenesis Regulation
Rate of gluconeogenesis is affected primarily by:
substrate availability
allosteric effectors
Hormones (e.g., cortisol and insulin)
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

20. Section 8.2: Gluconeogenesis
Cori Cycle: Lactate produced by anaerobic glycolysis in the muscles moves to the liver and is converted to glucose, which then returns to the muscles and is metabolized back to lactate.
Gluconeogenesis Substrates
Three of the most important substrates for gluconeogenesis are:
1. Lactate—released by skeletal muscle following exercise
After transfer to the liver lactate is converted to pyruvate, then to glucose
2. Glycerol—a product of fat metabolism. Must be converted to their intermediate glyceraldehyde 3-phosphate to produce glucose.
3. Alanine—generated from pyruvate in exercising muscle
Alanine is converted to pyruvate and then glucose in the liver
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

21. Allosteric Regulation
allosteric effectors may activate (+) or inhibit (-) steps along the metabolic pathways
GLUCONEOGENESIS 
GLYCOLYSIS 

22. Hormonal Regulation
The peptide hormones glucagon and insulin also regulate glycolysis/gluconeogenesis pathways
Glucagon is released by pancreatic alpha-cells when blood glucose is low; triggers a series of reactions that inhibit glycolysis and activate gluconeogenesis
Insulin is released by pancreatic beta-cells when blood glucose is high; triggers a series of reactions that activate glycolysis and inhibit gluconeogenesis

23. Pentose Phosphate Pathway
Alternate glucose metabolic pathway
Products are NADPH and ribose-5-phosphate
Two phases: oxidative and nonoxidative

24. Section 8.3: Pentose Phosphate Pathway
Alternate glucose metabolic pathway
Most active in cells where large quantities of lipids are synthesized (e.g., adipose tissue, adrenal cortex, mammary glands, liver)
Two phases: oxidative and nonoxidative
Oxidative phase:
Produces ribulose-5-phosphate and two NADPH (Nicotinamide adenine dinucleotide phosphate)
NADPH is a reducing agent used in anabolic (synthesis) processes (e.g., to produce lipids)
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

25. Oxidation Hydrolysis Pentose Phosphate Pathway – Oxidative Phase
Glucose-6-phosphate dehydrogenase
Gluconolactonase
Hydrolysis
Figure 8.15a The Pentose Phosphate Pathway (oxidative)
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

26. Oxidation Decarboxylation
Section 8.3: Pentose Phosphate Pathway
6-phosphogluconate dehydrogenase
Oxidation
Decarboxylation
Figure 8.15a The Pentose Phosphate Pathway (oxidative)
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

27. Section 8.3: Pentose Phosphate Pathway
Pentose Phosphate Pathway: Nonoxidative
Produces important intermediates for nucleotide biosynthesis and glycolysis
Ribose-5-phosphate
Glyceraldehyde-3-phosphate
Fructose-6-phosphate
Figure 8.15b The Pentose Phosphate Pathway (nonoxidative)
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

28. Section 8.3: Pentose Phosphate Pathway
If the cell requires more NADPH than ribose molecules, products of the nonoxidative phase can be shuttled into glycolysis
Figure 8.16 Carbohydrate Metabolism: Glycolysis and the Phosphate Pathway
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

29. Section 8.4: Metabolism of Other Important Sugars
22%
70%
Fructose, mannose, and galactose also important sugars for vertebrates
Most common sugars found in oligosaccharides besides glucose
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

30. Fructose Metabolism Section 8.4: Metabolism of Other Important Sugars
Second to glucose in the human diet
Found in fruit, honey, sucrose, high fructose corn syrup
Can enter the glycolytic pathway in two ways:
Through the liver (multi-enzymatic process)
Muscle and adipose tissue (hexokinase)
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

31. Section 8.4: Metabolism of Other Important Sugars
Figure 8.17 Carbohydrate Metabolism: Other Important Sugars
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

32. Section 8.5: Glycogen Metabolism
Glycogenesis
Synthesis of glycogen, the storage form of glucose, occurs after a meal
Requires a set of three reactions (1 and 2 are preparatory and 3 is for chain elongation):
1. Synthesis of glucose-1-phosphate (G1P) from glucose-6-phosphate by phosphoglucomutase
2. Synthesis of uridine diphosphate (UDP)-glucose from G1P by UDP-glucose phosphorylase
3. Synthesis of Glycogen from UDP-glucose
Requires two enzymes:
Glycogen synthase to grow the chain
Amylo-α(1,46)-glucosyl transferase which creates the α(1,6) linkages for branching
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

33. Section 8.5: Glycogen Metabolism
Figure 8.18 Glycogen Synthesis
Glycogen synthase
Glycogenesis Continued
Glycogen synthase catalyzes addition of glucose onto existing oligosaccharide by transferring glucosyl group of UDP-glucose to non-reducing end of glycogen
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

34. Section 8.5: Glycogen Metabolism
Branching enzyme
Glycogenesis Continued
Branching enzyme amylo-a(1,41,6)-glucosyl transferase creates a(1,6) linkages for branches that occur ~10 residues apart
a(1,6) Glycosidic Linkage is formed
Figure 8.18 Glycogen Synthesis
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

35. Glycogenolysis Section 8.5: Glycogen Metabolism
Glycogen degradation requires two reactions:
Removal of glucose from nonreducing ends (glycogen phosphorylase), which stops when four glucose units remain at the branch point (further degradation to the branch point results in a limit dextrin)
2. Hydrolysis of the a(1,6) glycosidic bonds at branch points by amylo-a(1,6)-glucosidase (debranching enzyme)
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

36. Section 8.5: Glycogen Metabolism
Glycogen phosphorylase uses organic phophate to cleave the a(1,4) linkages on the outer branches
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

37. Glycogenolysis Cont. Section 8.5: Glycogen Metabolism
amylo-a(1,6)-glucosidase first transfers the outer 3 glucose residues to a nearby non-reducing end, then uses water to hydrolyze the a(1,6) glycosidic bonds and remove the last glucose at the branch point
Amylo-a(1,6)-glucosidase
Amylo-a(1,6)-glucosidase
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

38. Section 8.5: Glycogen Metabolism
Amylo-a(1,6)-glucosidase
Glucose-1-phosphate, the major product of glycogenolysis, is diverted to glycolysis in muscle cells to generate energy for muscle contraction.
In hepatocytes, G1P is converted to glucose and released into the blood.
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

39. Section 8.5: Glycogen Metabolism
Regulation of Glycogen Metabolism
Carefully regulated by synthesis to maintain consistent energy levels
Regulation involves insulin, glucagon, epinephrine, and allosteric effectors
Figure 8.22 Major Factors Affecting Glycogen Metabolism
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

40. Section 8.5: Glycogen Metabolism
Glucagon activates glycogenolysis
Insulin inhibits glycogenolysis and activates glycogenesis
Epinephrine release activates glycogenolysis and inhibits glycogenesis
Figure 8.22 Major Factors Affecting Glycogen Metabolism
From McKee and McKee, Biochemistry, 5th Edition, © 2011 Oxford University Press

41. Regulation of Glycogen Metabolism
Glucagon is released from pancreas when blood glucose levels drop (e.g., after a meal). It binds to hepatocyte receptors, triggering a cascade of reactions that initiate glycogenolysis, releasing glucose into the bloodstream.
Insulin inhibits enzymes of glycogenolysis, and activates glycogenesis enzymes, increasing rate of glucose uptake.
Epinephrine, released due to emotional or physical stress, promotes glycogenolysis and inhibits glycogenesis; provides massive glucose release for flight-or-fight response.