Chapter 18: Storage Mechanisms and Control in Carbohydrate Metabolism

18.1 How Is Glycogen Produced and Degraded?

• Carbohydrates
o The “quick energy” that is needed by our body.
o When we eat carbs, our body breaks them down into simple sugars.
o The body can mobilize carbohydrates more easily than fat.
• Glycogen
o Rapid energy source.
o The stored form of glucose that is made of connected glucose molecules.
o Its structure is optimized for its ability to store and deliver energy quickly.
o The average chain length of its branches are 13 residues.
o Found primarily in liver and muscle
• Breakdown of Glycogen (Glycogenolysis)
o First Reaction: Phosphorolysis reaction catalyzed by Glycogen Phosphorylase

o Second Reaction: Isomerization; catalyzed by Phosphoglucomutase

o Summary of the First and Second Reactions:

▪ Glycogen phosphorylase cleaves the α (1,4) linkages.
▪ No ATP is hydrolyzed to ADP in this reaction.
▪ An alternative mode of entry to glycolytic pathway which saves one ATP for each
molecule of glucose.
▪ Net gain of 3 ATP per glucose (only if glycogen is the starting material in glycolysis)
o Third Reaction: Debranching; catalyzed by Debranching Enzymes
▪ Debranching Enzymes:
Transferase – moves 3 residues (limit branch) to the free end of the linear linkage
Glucosidase – hydrolyzes the α (1,6) remaining glucose residue that is linked to
the branch point
• Formation of Glycogen from Glucose (Glycogenesis)
o Glycogenesis requires energy which is provided by the hydrolysis of uridine
triphosphate (UTP).
 o In the first stage of glycogen synthesis, glucose-1-phosphate reacts with UTP to produce
uridine diphosphate glucose (UDP-glucose or UDPG) and pyrophosphate and
catalyzed by UDP-glucose pyrophosphorylase
o The supply of UTP is replenished by an exchange reaction with ATP, which is catalyzed
by nucleoside phosphate kinase
o The addition of UDPG to a growing chain of glycogen is the next step in glycogen
synthesis.
o The hydroxyl group of a specific tyrosine of the protein glycogenin acts as a primer which
initiates the glycogen synthesis.
o Glycogenin acts as a catalyst for addition of glucoses until there are about eight of them
linked together.
o At least 8 glucose molecules are linked before glycogen synthase takes over.
o Glycogen synthase catalyzes the addition of α (1,4) glucose linkages to the existing
chain.
o Glycogenesis also requires the formation of α (1,6) in which a branching enzyme
accomplishes this task.
o The branching enzyme catalyzes the transfer of 7 residues from the end of the growing
chain to a branch point in which it also catalyzes the formation of the required α (1,6)
glycosidic linkage.
o The transferred 7 residues must come from a chain of at least 11 residues long.
o The new branch point must be at least 4 residues away from the nearest existing branch
point.
• Control of Glycogen Metabolism
Control Mechanisms:
o Allosteric Control
 o Covalent Modification

▪ Glucagon and epinephrine are the hormones that triggers the enzyme
phosphorylase kinase.
▪ Phosphorylase kinase phosphorylates the dephosphorylated (inactive)
Glycogen phosphorylase b to give off an active form which is Glycogen
phosphorylase a, it also phosphorylates the active form of glycogen synthase
for it to be inactive.
▪ Glycogen phosphorylase a stimulates glycogenolysis
▪ Insulin is the hormone that triggers phosphoprotein phosphatase
▪ Phosphoprotein phosphatase dephosphorylates the phosphorylated (inactive)
glycogen synthase D to give off its active form which is glycogen synthase I, it
also dephosphorylates the active form of glycogen phosphorylase for it to be
inactive.
▪ Glycogen synthase I stimulates glycogenesis.

18.2 How Does Gluconeogenesis Produce Glucose from Pyruvate?

• Gluconeogenesis is the conversion of pyruvate to glucose.
• Gluconeogenesis is not the exact reversal of glycolysis.
• There are three irreversible steps in glycolysis:
o Production of pyruvate and ATP from phosphoenol pyruvate
o Production of fructose-1,6-bisphosphate from fructose-6-phosphate
o Production of glucose-6-phosphate from glucose
• Reactions of Gluconeogenesis:
o First Reaction: Catalyzed by Pyruvate carboxylase
 ▪ Requires energy which is provided by the hydrolysis of ATP.
▪ Pyruvate carboxylase is an allosteric enzyme found in mitochondria.
▪ Acetyl-CoA is an allosteric effector that activates the enzyme.
▪ Magnesium ion and biotin are also required for an effective catalysis.
▪ Biotin is a carrier of carbon dioxide.
▪ The carboxyl group of biotin forms an amide bond with the ϵ-amino group of a
specific lysine chain of pyruvate carboxylase.
▪ CO2 is attached to biotin, in which biotin is covalently bonded to pyruvate
carboxylase.
▪ After CO2 is attached to biotin, it then shifts to pyruvate to form oxaloacetate.
▪ ATP is required for this reaction.
o The oxaloacetate formed in mitochondria can have two fates:
1. Leave the mitochondria via a specific transporter to continue gluconeogenesis in the
cytosol.
2. It can be turned to malate via mitochondrial malate dehydrogenase.
o Second Reaction: Catalyzed by Phosphoenolpyruvate carboxykinase (PEPCK)

▪ Phosphoenolpyruvate carboxykinase (PEPCK) is found in the mitochondria and

cytosol.
▪ The reaction involves hydrolysis of GTP.
▪ The successive carboxylation and decarboxylation reactions are both close to
equilibrium.
o Third Reaction: Catalyzed by Fructose-1,6-bisphosphatase
 ▪ Fructose-1,6-bisphosphatase is an allosteric enzyme strongly inhibited by AMP
but stimulated by ATP.
▪ This enzyme is also inhibited by fructose-2,6-bisphosphate (a potent activator of
phosphofructokinase).
o Fourth Reaction: Catalyzed by Glucose-6-phosphatase
▪ The hydrolysis of glucose-6-phosphate to glucose occurs in the endoplasmic
reticulum.
18.2 How is Carbohydrate Metabolism Controlled?
• Control of Phosphofructokinase and Fructose-1,6-bisphosphatase
o Fructose-2,6-bisphosphate, allosteric activator of PFK-1 activity in the liver, is synthesized by
phosphofructokinase-2 (PFK-2) in response to hormonal signals correlated to blood glucose levels.
o AMP is an allosteric activator of PFK-1.
o AMP levels, which increase when the energy charge of the cell is low, are a better predictor of energy
deficit than ADP levels.
o PFK-1 is allosterically inhibited by high levels of ATP and citrate.
o High level of serum glucose, hormone-stimulated increase in fructose-2,6-bisphosphate
coordinately increases the activity of PFK-1 and decreases the activity of the enzyme that catalyzes
the reverse reaction, fructose-1,6-bisphosphatase
o AMP is an allosteric inhibitor of fructose-1,6-bisphosphatase.

• Fructose-2,6-bisphosphate level regulation

▪ The dephosphorylation reaction also inhibits FBP-ase-2, the enzymatic activity that
converts fructose-2,6-bisphosphate to fructose6-phosphate. Glycolysis is inhibited when
fructose-2-6-bisphosphate levels are low, which is the result of a glucagon-stimulated and
protein kinase A (PKA)-catalyzed phosphorylation reaction that inactivates PFK-2.
 • Lactate is produced anaerobically in muscle cells. After passing through blood to the liver,
lactate is converted to glucose by gluconeogenesis.

o Gluconeogenesis, the synthesis of new glucose molecules from noncarbohydrate precursors,

occurs primarily in the liver.
o Gluconeogenesis is an energy-consuming process. Instead of generating ATP (as in glycolysis),
gluconeogenesis requires the hydrolysis of six high energy phosphate bonds.

• Control of Pyruvate Kinase

 o major control point in glucose metabolism.
o It is inhibited by a high ATP concentration, and alanine.
o Pyruvate kinase is also found as isozymes with three different types of subunits:

• M, predominates in muscle
• L, in liver
• A, in other tissues

• Control of Hexokinase

o Hexokinase catalyze the phosphorylation of hexoses in all cells in the body.

o It is inhibited by high levels of its product, glucose-6-phosphate.
o Four important hexokinase isozymes:

1. Hexokinase I
✓ Found in brain tissue and red blood cells.
✓ It is free floating in the cytoplasm.
✓ Catabolic role for the use of Glucose-6-phosphate in energy production.
2. Hexokinase II
✓ Found in skeletal muscle, heart, and insulin sensitive tissues.
✓ Anabolic role, providing Glucose-6-phosphate for conversion to Glucose-1-
phosphate.
3. Hexokinase III
✓ Is substrate-inhibited by glucose at physiologic condition.
✓ Either not expressed or only minor expression within most tissues.
4. Hexokinase IV (Glucokinase)
✓ Found in liver and pancreas.
✓ Has higher Km than HK1 and HK2.
✓ It is not inhibited by the product, glucose-6-phosphate.

18.4 Why Is Glucose Sometimes Diverted through the Pentose Phosphate Pathway?

• Pentose Phosphate Pathway (PPP)

o It is an alternative metabolic pathway for glucose oxidation in which no ATP is generated.

o The glycolytic intermediates fructose-6-phosphate and glyceraldehyde-3-phosphate.
o It occurs in the cytoplasm in two phases:
 ▪ Oxidative phase, the conversion of glucose-6-phosphate to ribulose-5-phosphate is
accompanied by the production of two molecules of NADPH.
▪ Nonoxidative phase, involves the isomerization and condensation of a number of
different sugar molecules. When cells require more NADPH than pentose phosphates,
the enzymes in the nonoxidative phase convert ribose-5-phosphate into the glycolytic
intermediates fructose-6-phosphate and glyceraldehyde-3-phosphate
• Transketolase is a TPP requiring enzyme that transfers two-carbon units from a ketose to an
aldose.
• TPP, thiamine pyrophosphate, is the coenzyme form of thiamine, also known as vitamin B1.
• Transaldolase transfers three-carbon units from a ketose to an aldose.
• PPP principal products are:
o NADPH, a reducing agent required in several anabolic processes.
o Ribose-5-phosphate, a structural component of nucleotides and nucleic acids

• Control of pentose phosphate pathway

o The oxidative reactions at the beginning of the pathway are needed to produce NADPH.
The net reaction for the oxidative portion of the pathway is:
6 Glucose-6-phosphate + 12 NADP + 6 H 2 6 Ribose-5phosphate + 6 CO 2 + 12 NADPH + 12 H +
o If the cell requires more NADPH than ribose molecules, it can channel the products of the
non oxidative phase of the pentose phosphate pathway into glycolysis. As this overview
of the two pathways illustrates, excess ribulose-5-phosphate can be converted into the
glycolytic intermediates fructose-6- phosphate and glyceraldehyde-3-phosphate