CONCEPT MAP: THE GENERATION OF BIOCHEMICAL ENERGY
22.10 Glycogen Metabolism: Glycogenesis and Glycogenolysis
Glycogen, the storage form of glucose in animals, is a branched polymer of glucose.
Glycogen synthesis, known as glycogenesis, occurs when glucose concentrations are high. It begins with glucose 6-phosphate and occurs via the three steps shown on the right in Figure 22.8.
Glucose 6-phosphate is first isomerized to glucose 1-phosphate by phosphoglucomu- tase. The glucose residue is then attached to uridine diphosphate (UDP) in a reaction catalyzed by UDP-glucose pyrophosphorylase and driven by the release of inorganic pyrophosphate. The pyrophosphate (diphosphate) is then hydrolyzed, yielding two hydrogen phosphate ions (see Worked Example 22.3).
CH2OH O
OH HO OH O
H
H H
H H
O− P O
O O−
P O
O Uridine Glucose-UDP, the activated carrier of glucose in glycogen synthesis Glycogenesis The biochemical
pathway for synthesis of glycogen, a branched polymer of glucose.
S E C T I O N 2 2 . 1 0 Glycogen Metabolism: Glycogenesis and Glycogenolysis 711
The resulting glucose-UDP transfers glucose to a growing glycogen chain in an exergonic reaction catalyzed by glycogen synthase.
As is usually true in metabolism, synthesis and breakdown are not accom- plished by exactly reverse pathways. Glycogenolysis occurs in the two steps on the left in Figure 22.8. The first step is formation of glucose 1-phosphate by the action of glycogen phosphorylase on a terminal glucose residue in glycogen. Glucose 1-phosphate is then converted to glucose 6-phosphate by phosphoglucomutase in the reverse of the reaction by which it is formed. These reactions occur inside liver and muscle cells and are different from the reactions involved in the hydro- lysis of glycogen during the digestion of muscle that you have eaten, perhaps in a hamburger.
In muscle cells, glycogenolysis occurs when there is an immediate need for energy.
The glucose 6-phosphate produced from glycogen breakdown never leaves the cell, instead going directly into glycolysis to generate energy. In the liver, glycogenolysis occurs when blood glucose is low (for example, during starvation; see Section 22.8).
Because glucose 6-phosphate cannot cross cell membranes, liver cells contain glucose 6-phosphatase, an enzyme that hydrolyzes glucose 6-phosphate to free glucose, which can then be released into the bloodstream to raise blood sugar levels.
Glycogenolysis The biochemical path- way for breakdown of glycogen to free glucose.
ATP
Step 1 of glycolysis
Glycolysis
Glycogenesis Glycogen
phosphorylase Glycogenolysis
(Glucose)n [Glycogen]
(Glucose)n − 1
(Glucose)n − 1 Phosphoglucomutase
ADP
Uridine triphosphate (UTP)
2 HOPO32−
HOPO32−
UDP Glucose 1-phosphate
Glucose 6-phosphate
Glucose–UDP Glucose
▲ Figure 22.8
Glycogenolysis and glycogenesis.
Reading from the top down shows the pathway for glycogen synthesis from glucose (glycogenesis). Reading from the bottom up shows the pathway for release of glucose from glycogen (glycogenolysis).
The Biochemistry of Running
A runner is poised tense and expectant, waiting for the sound of the starting gun. Long hours of training have prepared heart, lungs, and red blood cells to deliver the maximum amount of oxygen to the muscles, which have been conditioned to use it as efficiently as possible. In the moments before the race, mount- ing levels of epinephrine have readied the body for action. Now, everything depends on biochemistry: chemical reactions in mus- cle cells will provide the energy to see the race through. How will that energy be produced?
The first source is the supply of immediately available ATP, but this is used up very quickly—probably within a matter of seconds. Additional ATP is then provided by the reaction of ADP with creatine phosphate, an amino acid phosphate in muscle cells that maintains the following equilibrium:
ADP + Creatine phosphate m ATP + Creatine After about 30 seconds to a minute, stores of creatine phos- phate are depleted, and glucose from glycogenolysis becomes the chief energy source. During maximum muscle exertion, oxygen cannot enter muscle cells fast enough to keep the cit- ric acid cycle and oxidative phosphorylation going. Under these anaerobic conditions, the pyruvate from glycolysis is converted to lactate rather than entering the citric acid cycle.
In a 100 m sprint, all the energy comes from available ATP, creatine phosphate (CP in the figure), and glycolysis of glucose
Lactate
Lactate
Pyruvate
To myofibrils to support muscle contraction
Glycogen To liver
ATP ATP ADP ADP 2
2 CP
Creatine Glucose
▲At peak activity, ATP formation relies on creatine phosphate (CP) and glucose from muscle glycogen. Pyruvate is converted to lactate, which enters the bloodstream for transport to the liver, where it is recycled to pyruvate.
from muscle glycogen. Anaerobic glycolysis suffices for only a minute or two of maximum exertion, because a buildup of lac- tate causes muscle fatigue.
Beyond this, other pathways must come into action. As breathing and heart rate speed up and oxygen-carrying blood flows more quickly to muscles, the aerobic pathway is activated and ATP is once again generated by oxidative phosphorylation.
The trick to avoiding muscle exhaustion in a long race is to run at a speed just under the “anaerobic threshold”—the rate of exertion at which oxygen is in short supply, ATP is supplied only by glycolysis, and lactate is produced.
Now the question is, which fuel will metabolism rely on dur- ing a long race—carbohydrate or fat? Burning fatty acids from fats is more efficient. More than twice as many calories are generated by burning a gram of fat than by burning a gram of carbohydrate. When we are sitting quietly, in fact, our muscle cells are burning mostly fat, and the fat in storage could support the exertion of marathon running for several days. By contrast, glycogen alone can provide enough glucose to fuel only two to three hours of such running under aerobic conditions.
The difficulty is that fatty acids cannot be delivered to muscle cells fast enough to maintain the ATP level needed for running, so metabolism compromises and the glycogen stored in muscles remains the limiting factor for the marathon runner. Once glyco- gen is gone, extreme exhaustion and mental confusion set in—the condition known as “hitting the wall.” Running speed is then lim- ited to that sustainable by fats only. To delay this point as long as possible, a runner encourages glycogen synthesis by a diet high in carbohydrates prior to and during a race. In the hours just before the race, however, carbohydrates are avoided. Their effect of trig- gering insulin release is undesirable at this point because the result- ing faster use of glucose will hasten depletion of glycogen.
See Chemistry in Action Problems 22.79 and 22.80 at the end of the chapter.
CHEMISTRY IN ACTION
▲ The energy used by these runners is fueled by glycogen stores. The stored glucose is converted to energy through gly- colysis, the citric acid cycle and the electron transport system.
S E C T I O N 2 2 . 1 1 Gluconeogenesis: Glucose from Noncarbohydrates 713
Worked Example 22.3 Analyzing a Reaction
The following overall reaction is a good example of the coupling of endergonic and exergonic reactions:
UTP + Glucose 1@phosphate + H2O h Glucose@UDP + 2 HOPO32- The coupled reactions are
UTP + Glucose 1@phosphate h
Glucose@UDP + OP2O64- ⌬G = 1.1 kcal>mol 14.6 kJ>mol2 OP2O64- + H2O h 2 HOPO32- ⌬G = -8.0 kcal>mol 1-33.5 kJ>mol2 What is the common intermediate in these coupled reactions? What is ⌬G for the coupled reactions? Based on these ⌬G values, is the change favorable or unfavorable?
ANALYSIS To find the common intermediate, look for a moiety that appears on the left-hand side of one of the equations and on the right-hand side of the other. In this case OP2O64- (pyrophosphate or diphosphate) appears in each equation, but on opposite sides. It must be the common intermediate. To determine the ⌬G for the coupled reactions, simply add the ⌬Gs. If the sign of the sum is negative, the reaction is exergonic and favored; if the sign of the sum is positive, the reaction is endergonic and unfavored.
SOLUTION
Inspection of the coupled reactions shows OP2O64- to be the common intermediate because it appears on opposite sides of the arrow in the two reactions. The sum of the ⌬Gs is -6.9 kcal>mol 1-28.9 kJ>mol2. The reaction is exergonic and is favored.
PROBLEM 22.16
Why is creatine phosphate a better source of quick energy for a runner than either glu- cose or glycogen? (See Chemistry in Action: The Biochemistry of Running, p. 712.)