Glycogen Breakdown. Glycogen Breakdown. Storage Mechanisms and Control of Carbohydrate Metabolism. Glycogen Breakdown. Glycogen from Glucose

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1 Glycogen Breakdown Storage Mechanisms and Control of Carbohydrate Metabolism Glycogen is cleaved by to give -Dglucose-1- no ATP is involved in this phosphorylation (Glucose) n + - P 3 Glycogen (Glucose) n glycogen phosphorylase 肝 醣 磷 酸 化 脢 C 2 P 3 -D-Glucose-1- Glycogen Breakdown Glycogen Breakdown Enzyme-catalyzed isomerization converts the 1- to the 6- C 2 P 3 -D-Glucose-1- phosphoglucomutase 磷 酸 葡 萄 糖 變 位 脢 -D-Glucose-6- Figure 15.2 The action of glycogen debranching enzyme Glycogen from Glucose Glucose 1- reacts with uridine tri to give UDPG and pyro Glucose-1- + UTP UDP-glucose pyrophosphorylase UDP- 葡 萄 糖 焦 磷 酸 化 脢 C 2 N N -P- -P C Uridine di glucose (UDPG ) UDP G + PP i Glycogen from Glucose Coupling of UDPG formation with hydrolysis of pyro drives formation of UDPG to completion G? (kj ol -1 ) Glucose-1- + UTP UDPG + PP i?0 PP i + 2 2P i Glucose-1- + UTP + 2 UDPG + 2P i

2 Glycogen from Glucose Branching of glycogen uridine di glucose (UDPG) then adds its glucose unit to the growing glycogen chain (Glucose) n + Glycogen new glucose unit added UDP G glycogen synthase -Glucose- (Glucose) n + UDP exchange of with ATP regenerates UTP UDP + ATP nucleoside kinase UTP + ADP Structure of glycogen phosphorylase Control of Glycogen Metab Figure 15.5 Glycogen phosphorylase - a major control point Control of Glycogen Metab The activity of glycogen synthase is subject to the same type of covalent modification as glycogen phosphorylase the response, however, is opposite hormonal signals (glucagon or epinephrine) stimulate its phosphorylation once phosphorylated, glycogen synthase becomes inactive 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 Activation of glycogen phosphorylase and inactivation of glycogen synthase 2

3 Activation of glycogen synthase and inactivation of glycogen phosphorylase : the synthesis of glucose from pyruvate gluconeogenesis is not the exact reversal of glycolysis; that is, pyruvate to glucose does not occur by reversing the steps of glucose to pyruvate there are three irreversible steps in glycolysis ---phosphoenolpyruvate to pyruvate + ATP ---fructose-6- to fructose-1,6-bis ---glucose to glucose-6- the net result of gluconeogenesis is reversal of these three steps, but by different reactions and using different enzymes Step 1: carboxylation of pyruvate requires biotin pyruvate carboxylase is subject to allosteric control; it is activated by acetyl-coa C 3 CC - Pyruvate + C 2 + ATP biotin pyruvate carboxylase C 2 CC - + ADP + P i C - xaloacetate Biotin Biotin is a carrier of carbon dioxide N N S Biotin C - C N N S 1. 2 N- enzyme 2. C 2 + AT P N-enz yme C decarboxylation of oxaloacetate is coupled with phosphorylation by GTP to give PEP C 2 CC - + GTP - C 2 xaloacetate P 3 C 2 = CC - Phosphoenolpyruvate + C 2 + GDP the net reaction of carboxylation/decarboxylation is Pyruvate + ATP + GTP Phosphoenolpyruvate + ADP + GDP + P i net reaction is close to equilibrium: G 0 = 2.1 kj mol -1 3

4 Second different reaction in gluconeogenesis + 2 -D-Fructose-1,6-bis fructose 1,6-bisphosphatase Mg 2 + C 2 + P i -D-Fructose-6- G = kj mol -1 fructose-1,6-bisphosphatase is an allosteric enzyme, inhibited by AMP and activated by ATP Third different reaction in gluconeogenesis G = kj mol -1 Allosteric: fructose-2,6-bis (F2,6P) an allosteric activator of phosphofructokinase (PFK) an allosteric inhibitor of fructose bis phosphatase (FBPase) high concentration of F2,6P stimulates glycolysis; a low concentration stimulates gluconeogenesis concentration of F2,6P in a cell depends on the balance between its synthesis (catalyzed by phosphofructokinase-2) and its breakdown (catalyzed by fructose bisphosphatase-2) each enzyme is controlled by phosphorylation/dephosphorylation Figure The inhibition of fructose-1,6-bis Allosteric Covalent modification Substrate cycles Genetic Effectors (substrates, products, or coenzymes) of a pathway inhibit or activate an enzyme Inhibition or activation of an enzyme depends on formation or breaking of a covalent bond, often by phosphorylation or dephosphorylation Two opposing reactions (such as formation or breakdown of a substance) are catalyzed by different enzymes, which are activated or inhibited separately The amount of enzyme present is increased by protein synthesis Substrate cycling opposing reactions can be catalyzed by different enzymes and each opposing enzyme or set of enzymes can be regulated independently C 2 glucose-6- phosphatase P i -D-Glucose-6- -D-Glucose G 0' phosphofructokinase (kj ol -1 ) Fructose-6- + ATP Fructose 1,6-bis + ADP fructose-1,6- bisphosphatase Fructose 1,6-bis + 2 Fructose-6- + P i

5 The Cori Cycle The Cori cycle under vigorous anaerobic exercise, glycolysis in muscle tissue converts glucose to pyruvate; NAD + is regenerated by reduction of pyruvate to lactate lactate from muscle is transported to the liver where it is reoxidized to pyruvate and converted to glucose thus, the liver shares the stress of vigorous exercise Figure The Cori cycle Control of Pyruvate Kinase Pyruvate kinase (PK) is an allosteric enzyme inhibited by ATP and alanine activated by fructose-1,6-bis PK isoenzymes have 3 different subunits M predominates in muscle, L in liver, and A in other tissues native PK is a tetramer the liver isoenzymes are subject to covalent modification Control of exokinase inhibited by high levels of glucose 6- when glycolysis is inhibited through phosphofructokinase, glucose 6- builds up, shutting down hexokinase as the name implies, five-carbon sugars, including ribose, are produced from glucose the oxidizing agent is NADP + ; it is reduced to NADP, which is a reducing agent in biosyntheses begins with two oxidation steps (NADP + ) to give ribulose-5- there follows a series of carbon-shuffling steps during which three-, four-, five-, six-, and seven-carbon monosaccharide s are produced C C - NADP + NADP NADP + NADP Glucose-6-6-Phosphogluconate 6 - 磷 酸 葡 萄 糖 糖 酸 C - C 2 + C 2 Ribulose-5- 核 酮 糖 -5- 磷 酸 5

6 Nicotinamide adenine dinucleotide xidative Reaction of Non-xidative Reaction of C 2 Ribulose-5- 核 酮 糖 -5- 磷 酸 核 糖 -5- 磷 酸 C Ribose-5- C 2 Xylulose-5- 木 酮 糖 -5- 磷 酸 C 2 Sedoheptulose- 7- 景 天 庚 酮 糖 -7- 磷 酸 C Glyceraldehyde- 3- 甘 油 醛 -3- 磷 酸 Non-xidative Reaction of C 2 Sedoheptulose-7- 景 天 庚 酮 糖 -7- 磷 酸 C Glyceraldehyde-3- 甘 油 醛 -3- 磷 酸 原 藻 醛 糖 -4- 磷 酸 C Erythrose-4- C 2 Fructose-6- 果 糖 -6- 磷 酸 C 2 Xylulose-5- C Erythrose- 4- C Glyceraldehyde- 3- C 2 Fructose-6-6

7 the carbon-shuffling reactions are catalyzed by ---transketolase for the transfer of two-carbon units and ---transaldolase for the transfer of three-carbon units transketolase requires thiamine pyro Control of the pentose pathway glucose-6- (G6P) can be channeled into either glycolysis or the pentose pathway if ATP needed, G6P is channeled into glycolysis if NADP or ribose-5- are needed, G6P is channeled into the pentose pathway Summary Reactant Enzyme Products C 5 + C 5 Transketolase C 7 + C 3 C 7 + C Transaldolase 3 C 6 + C 4 C 5 + C Transketolase 4 C 6 + C 3 Net: 3 C 5 2 C 6 + C 3 7