Glycogen Breakdown

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) • 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 phosphorylasekinase • Dephosphorylation is by phosphoproteinphosphatase

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: 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 ________________ (CO2 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 + Pi

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° = -16.7•kJ 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 + Pi Both Reactions are exergonic, and the net reaction is ATP +H2O <--> ADP + Pi

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