Exam 3 Lecture #2: Glycogen Metabolism

Question 1

Glycogen is composed of mainly glycosyl linkages, mostly linked by ______ linkages.

Branches arise frequently from ______ linkages.

Answer 1

Glycogen is composed of mainly glycosyl linkages, mostly linked by alpha 1,4 linkages,

Branches arise frequently from alpha 1,6 linkages.

Question 2

Draw the diagram on what happens to liver glycogen levels between meals and during the nocturnal fast.

Answer 2

Question 3

Explain Glycogen Synthesis in the Liver:

_________ is the key enzyme which adds glucose-1-P to the growing glycogen chain

The liver can store about ______ of glycogen.

What happens when that limit is reached?

Answer 3

Glycogen Synthesis in the Liver:

Glycogen Synthase is the key enzyme which adds glucose-1-P to the growing glycogen chain.

The liver can store about 100g of glycogen.

Once that amount is stored, excess glucose is redirected towards fatty acid synthesis.

Question 4

Explain glycogen degradation in the liver:

________ is the key enzyme involved in removing glucose from glycogen.

The liver expresses the enzyme ___________

Answer 4

Glycogen Degradation in the Liver:

Glycogen Phosphorylase is the key enzyme involved in removing glucose from glycogen.

Liver expresses the enzyme glucose-6-phosphatase.

Question 5

Which enzyme does the liver express but muslce does not express in terms of glycogen degradation?

Answer 5

Muscle does not express glucose 6 phosphatase.

Question 6

Muscle Glycogen Synthesis and Degradation:

Muscle can store up to ______ of glycogen.

Excess muscle glucose converted to _______

Answer 6

Muscle can store up to 400g of glycogen.

Excess muscle glucose converted to Fatty Acids and stored as triacylglycerols.

Question 7

When does muscle glycogen get used?

Answer 7

Muscle glycogen NOT used to increase plasma glucose levels during hypoglycemia.

Degradation of muscle glycogen stimulated by EPI or muscle contraction to be used during exercise/fight or flight.

Question 8

Glucose transporter in liver vs glucose transporter in muscle

Answer 8

GLUT 2: liver

GLUT 4: muscle

Question 9

Explain the sequence of energy sources during exercise? Aka what gets used first, second, etc

Answer 9

1. ATP and creatine phosphate (first few seconds)
2. Anaerobic Glycolysis: muscle glycogen (minutes 1-5)
3. Aerobic Oxidation (muscle glycogen, plasma glucose, liver glycogen)
4. Aerobic Oxidation (plasma FFA, adipose tissue TAGs)

Question 10

What energy currency is used during glycogen formation?

Draw the triangle connecting glucose-6-P to glycogen formation and degradation

Answer 10

UDP is used during glycogen formation

Question 11

What are the two enzymes that Glycogen Synthesis requires?

Answer 11

Glycogen Synthesis Requires:

1. Glycogen Synthase : adds glucosyl units in an alpha 1, 4 linkage
2. Branching Enzyme: adds glucosyl units in an alpha 1, 6 linkage

Question 12

How many glucose units are between branch points?

Answer 12

10-14 glucosyl units in between branch points in glycogen

Question 13

Which protein serves as a primer for glycogen synthesis?

Answer 13

Glycogenin serves as a primer for glycogen synthesis

Question 14

What enzymes are required for Glycogen Degradation?

Answer 14

Glycogen Degradation Requires:

1. Glycogen Phosphorylase (removes glucosyl units from alpha 1, 4 linkage)
2. Debranching Enzyme (transferase and alpha 1,6 glucosidase)
3. Additional Kinases are used to activate the glycogen phosphorylase

Question 15

What are the three second messenger systems that play a role in the regulation of glycogen metabolism?

Answer 15

Regulation of Glycogen Metabolism:

Second Messenger Systems:

• cAMP
• PI, IP3
• Calcium

Question 16

How to the three messenger systems activate glycogen breakdown?

Answer 16

Three second messenger systems, i.e. cAMP, PI and Ca2+ activate glycogen phosphorylase by activating phosphorylase kinase, which phosphorlyates and activates glycogen phosphorylase….. leading to glycogen degradation

Question 17

Glycogen phosphorylase is “active” in which form?

Answer 17

Glycogen phosphorylase is active when it gets phosphorylated by the kinase (this state is also known as phosphorylase a)

think “a” means activated

Question 18

What does cAMP do to help promote glycogen degradation?

Answer 18

cAMP activates protein kinase A, which in turn P/activates the phosphorylase kinase, which then in turn also activates the glycogen phosphorylase.

cAMP also inhibts the phosphoprotein phosphatase

Question 19

How does glucagon promote glycogen degradation?

Answer 19

Glucagon promotes the activation of glycogen phosphorylase by activating the kinase, AND by phosphorylating/inhibiting the phosphatase

Question 20

How does calcium play a role in regulation?

Answer 20

Calcium is necessary for the phosphorylase kinase to work

Question 21

Explain GSD V and VI

Answer 21

GSD V and VI: Defeciency of Glycogen Phosphorylase…the pt will not be able to utilize glycogen, and therefore during the fasting state the pt will have increased ketone bodies in the blood

(can’t use glycogen so you mobilize beta oxidation of fatty acids)

Question 22

Insulin inhibits glycogen degradation by____

Answer 22

Insulin inhibits glycogen phosphorylation by causing the enzyme to be dephosphorylated and inactivated.

Question 23

What are the effects of AMP, Glucose and ATP on glycogen phosphorylase?

Answer 23

High levels of AMP (like during exercise) will cause AMP to directly bind to the “b”/inactivated form of the phosphorylase, resulting in a conformational change to make the phosphorylase change to an active form, overriding the negative effect of ATP.

Similarly, when glucose and ATP levels are high they can find to the active/”a” form and cause it to become inactive.

Question 24

Insulin promotes glocogen storage or degradation?

How does it do that

Answer 24

Insulin promotes glycogen storage

Insulin inhibits glycogen phosphorylase by causing the enzyme to be dephosphorylated and therefore inactivated

Question 25

Glycogen synthase is active in its _____ form

Answer 25

Glycogen synthase is active in its DEPHOSPHORYLATED form (called “glycogen synthase a”)

Question 26

Insulin promotes glycogen degradation or storage…. affect on glycogen synthase?

Answer 26

Insulin promotes glycogen storage, therefore it will ACTIVATE the phosphoprotein phosphatase, causing the glycogen synthase to be active form (dephosphorylated)

Question 27

What does cAMP and calcium do to glycogen synthase?

Answer 27

cAMP, calcium, and Diacylglycerol cause glycogen synthase to be deactivated (aka make it phosphorylated and its in “b” form)

Question 28

Glycogen synthase is inhibited when phosphorylated:

Affects of glucagon on glycogen synthase?

Answer 28

Glycogen synthase is inhibited when phosphorylated

Glucagon (cAMP inhibits phosphatase, keeping the glycogen synthase in its inactivated/phosphorylated form)

Question 29

Explain the allosteric affect high levels of glucose-6-P has on glycogen synthase?

Answer 29

High glucose 6-P levels (like in GSD I or von Gierke’s disease)

will bind directly to the inactive/”b” form, causing a conformational change… making glycogen synthase active

Question 30

Explain how cAMP in the liver affects:

glycogen degradation

glycolysis

glycogen synthesis

Answer 30

High cAMP in the liver:

Remember, that means glucagon

• promotes glycogen degradation
• inhibits glycolysis
• inhibits glycogen synthesis

Question 31

Explain how cAMP in the heart and skeletal muscle affects:

glycogen degradation

glycolysis

glycogen synthesis

Answer 31

cAMP in heart and skeletal muscle:

remember that means glucagon

• promotes glycogen degradation
• activates glycolysis (remember due to PFK-2)
• inhibits glycogen synthesis

Question 32

Explain how IP3 and Calcium mediate the stimulation of glycogenolysis in the liver via alpha agonists

Answer 32

• IP3 increases calcium

Calcium activates Ca-dependent protein kinase C

-(DAG also activates PKC)

PKC then promotes glycogen breakdown/glycogenolysis

Question 33

What do Glycogen Storage Diseases affect?

Answer 33

Glycogen Storage Diseases can affect:

• Tissue concentration of glycogen
• Fasting blood glucose levels
• Lipid Metabolism

Question 34

Glucagon and Epi promote glucose homeostatis:

• Raise/lower blood glucose levels
• Promote/inhibit hepatic gluconeogenesis
• Promote/inhibit hepatic glycogen degradation
• Block/allow hepatic utilization of glucose
• Promote/inhibit hepatic glycolysis
• Promote/inhibit hepatic glycogen synthesis

Answer 34

Glucagon and Epi:

• Raise blood glucose levels
• Promote hepatic gluconeogenesis
• Promote hepatic glycogen degradation
• Block hepatic utilization of glucose
• Inhibit hepatic glycolysis
• Inhibit hepatic glycogen synthesis

Question 35

Which two enzymes does Glucagon and Epi directly affect to inhibit hepatic glycolysis?

Answer 35

Glucagon and Epi:

• Inhibit PFK-2….. indirectly inhibiting PFK-1
• Directly inhibit pyruvate kinase

Question 36

How do glucagon and epi activate gluconeogenesis in the liver?

Answer 36

Glucagon and Epi activate gluconeogenesis in the liver by:

Inhibut PFK-2… F-1,6-bisphosphatase

Inhibit pyruvate kinase (which promotes gluconeogenesis by inhibiting glycolysis)

Question 37

The Pentose Phosphate Pathway/Hexose Monophosphate Shunt

What does it generate in RBCs?

Answer 37

The Pentose Phosphate Pathway:

Generates (RBCs):

• NADPH
• Ribose-5-P (intermediates)
• Purine Biosynthesis (DNA, RNA, CoA)

Question 38

What is the rate limiting enzyme of the Pentose Phosphate Pathway?

Answer 38

The rate limiting enzyme of the Pentose Phosphate Pathway is Glucose 6-P Dehydrogenase

which takes glucose 6-P and turns it into 6-phosphogluconate

Note: this reaction creates NADPH

Question 39

The pentose phosphate pathway eventually generates intermediates of ______

Answer 39

The pentose phosphate pathway eventually generates intermediates of glycolysis

Question 40

Explain what a genetic deficiency of the Glucose 6-Phosphate Dehydrogenase does

Answer 40

A genetic deficiency of G6PDH is associated with drug induced hemolytic anemia.

_(_decreased hemoglobin, increased hemolytic anemia)