Chapter 18Storage Mechanisms and Control in

Carbohydrate Metabolism

Mary K. CampbellShawn O. Farrellhttp://academic.cengage.com/chemistry/campbell

Paul D. Adams • University of Arkansas

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

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

Debranching Glycogen

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 _______________________

How is Glycogen formed from Glucose?

• Coupling of UDPG formation with hydrolysis of ____________________________ drives formation of UDPG to completion

Reaction Catalyzed by Glycogen Synthase

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

Control of Glycogen Metabolism (Cont’d)

• The activity of glycogen synthaseglycogen 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

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

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 __________________

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 _______________________

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

Pyruvate Carboxlyase Reaction

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

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

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

Synthesis and Breakdown of F2,6P

Mechanisms of Metabolic Control

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

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

The Cori Cycle

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

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

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

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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

Group Transfer Reactions

Relationship between PPP and Glycolysis