1. Chapter 18 Storage Mechanisms and Control in Carbohydrate Metabolism Mary K. Campbell Shawn O. Farrell http://academic.cengage.com/chemistry/campbell Paul D. Adams University of Arkansas

2. Glycogen Breakdown Glycogen is cleaved by phosphate to give  Cleavage reaction is ______________________, not hydrolysis No _______ is involved in reaction Reaction is catalyzed by glycogen phosphorylase

3. Glycogen Breakdown In the second reaction, glucose-1-phosphate is isomerized to __________________________ This reaction is catalyzed by phosphoglucomutase Complete breakdown requires debranching enzymes to degrade the  linkages

4. Debranching Glycogen

5. How is Glycogen formed from Glucose? Not exact reversal of glycogen breakdown to glucose Glycogen synthesis requires energy Energy supplied by hydrolysis of ___________________ Glucose-1-phosphate reacts with UTP to make UDPG Pyrophosphate is also formed UDPG is then added to a growing chain of glycogen, catalyzed by glycogen _______________________

6. How is Glycogen formed from Glucose? Coupling of UDPG formation with hydrolysis of ____________________________ drives formation of UDPG to completion

7. Reaction Catalyzed by Glycogen Synthase

8. Control of Glycogen Metabolism Glycogen phosphorylase is a major control point in the synthesis and breakdown of glycogen Glycogen phosphorylase activity can be allosterically controlled, as well as, controlled through _________ modification

9. Control of Glycogen Metabolism (Cont’d) glycogen synthase The activity of glycogen synthase is subject to the same type of covalent modification as glycogen phosphorylase, but the response is opposite In addition: Hormonal signals (glucagon or epinephrine) _______ its phosphorylation After phosphorylation, glycogen synthase becomes __________ at the same time the hormonal signal is activating phosphorylase Glycogen synthase can be phosphorylated by several other enzymes including phosphorylase kinase Dephosphorylation is by phosphoprotein phosphatase

10. Summary Glycogen is the storage form of glucose in animals, including humans. Glycogen releases glucose when energy demands are high Glucose polymerizes to form glycogen when the organism has no immediate need for the energy derived from glucose breakdown Glycogen metabolism is subject to several different control mechanisms, including covalent modification and allosteric effects

11. Gluconeogenesis Gluconeogenesis: Gluconeogenesis: pyruvate → glucose Gluconeogenesis is __________________________ of glycolysis; that is, pyruvate to glucose does not occur by reversing the steps of glucose to pyruvate Three irreversible steps in glycolysis - Phosphoenolpyruvate to pyruvate + ATP - Fructose-6-phosphate to fructose-1,6-bisphosphate - Glucose to glucose-6-phosphate Net result of gluconeogenesis is reversal of these three steps, but by different __________________ and using different __________________

12. Oxaloacetate is an Intermediate In first step, pyruvate is carboxylated to oxaloacetate Requires ________________ (CO 2 carrier) Pyruvate carboxylase is subject to allosteric control; it is activated by _______________________

13. Gluconeogenesis (Cont’d) Next, decarboxylation of oxaloacetate is coupled with phosphorylation by ___________ to give PEP The net reaction of carboxylation/decarboxylation is Pyruvate + ATP +GTP → Phosphenolpyruvate + ADP + GDP + P i

14. Pyruvate Carboxlyase Reaction

15. Role of Sugar Phosphates Other different reactions in gluconeogenesis relative to glycolysis involve phosphate-ester bonds bound to sugar-hydroxyl groups being hydrolyzed  G° = -16.7kJ mol -1 Fructose-1,6-bisphosphatase is an ________ enzyme, inhibited by AMP and activated by ATP

16. Role of Sugar Phosphates (Cont’d) Another reaction is the hydrolysis of glucose-6-phosphate to ___________ and _______ Reaction also spontaneous (  G°’ = -13.8 kJ mol -1 ) Reaction catalyzed by glucose-6-phosphatase

17. Control of Carbohydrate Metabolism Allosteric control: fructose-2,6-bisphosphate (F2,6P) An allosteric ________ of phosphofructokinase (PFK) An allosteric ________ of fructose bisphosphate phosphatase (FBPase) High concentration of F2,6P stimulates __________ ; a low concentration stimulates ____________ Concentration of F2,6P in a cell depends on the balance between _________________ (catalyzed by phosphofructokinase-2) and _______________ (catalyzed by fructose bisphosphatase-2) Each enzyme is controlled by phosphorylation/dephosphorylation

18. Synthesis and Breakdown of F2,6P

19. Mechanisms of Metabolic Control

20. Substrate Cycling Substrate cycling opposing reactions can be catalyzed by different enzymes and each opposing enzyme or set of enzymes can be ________________________ Fructose-6-Phosphate + ATP → Fructose-1,6,-bisphosphate + ADP Fructose-1,6,-bisphosphate + ADP → Fructose-6-Phosphate + P i Both Reactions are exergonic, and the net reaction is ATP +H 2 O ADP + P i

21. Organs Share Carbohydrate Metabolism The Cori cycle Under vigorous ____________ ____________, glycolysis in muscle tissue converts glucose to pyruvate; NAD + is regenerated by reduction of pyruvate to lactate Lactate from muscle is transported to the _________, reoxidized to pyruvate, and converted to glucose The liver shares the stress of vigorous exercise

22. The Cori Cycle

23. Control Points in Carbohydrate Metabolism First and last steps in glycolysis are major control points in glucose metabolism ________________________ Inhibited by high levels of glucose 6-phosphate When glycolysis is inhibited through phosphofructokinase, glucose 6-phosphate builds up, shutting down hexokinase ________________________ (PK) is an allosteric enzyme Inhibited by ATP and alanine Activated by fructose-1,6-bisphosphate ________________________ have 3 different subunits M predominates in muscle, L in liver, and A in other tissues Native PK is a tetramer Liver isoenzymes are subject to covalent modification

24. Summary A number of control mechanisms operate in carbohydrate metabolism. These include allosteric effects, covalent modification, substrate cycles, and genetic control In the mechanism of substrate cycling, the synthesis and the breakdown of a given compound are catalyzed by two different enzymes

25. The Pentose Phosphate Pathway The Pentose Phosphate Pathway (PPP) is an alternative to __________________, and differs in several ways In glycolysis, ATP production is important, in PPP, _________________________________ As the name implies, ____________ sugars, including ribose, are produced from glucose Oxidizing agent is NADP + ; it is reduced to NADPH, which is a reducing agent in biosyntheses Begins with two oxidation steps (NADP + ) to give ____________________________________ Following this, a series of ___________________________ occur during which three-, four-, five-, six-, and seven-carbon monosaccharide phosphates are produced

26. The Pentose Phosphate Pathway

27. Control of the Pentose Phosphate Pathway The carbon-shuffling reaction are catalyzed by: ________________________ for the transfer of two-carbon units and ________________________ for the transfer of three-carbon units Control of the PPP is maintained by: Glucose-6-phosphate (G6P) can be channeled into either glycolysis or the pentose phosphate pathway G6P channeling into glycolysis, if ________________ G6P channeling into the pentose phosphate pathway, if _________ or __________________ are needed

28. Group Transfer Reactions

29. Relationship between PPP and Glycolysis