Glycogen Synthesis & Degradation, Pentose Phosphate Pathway

Question 1

What are the key outputs of the pentose phosphate pathway?

Answer 1

NADPH and Ribose 5 Phosphate. NADPH is used in alcohol detoxification, fatty acid synthesis, neurotransmitter synthesis. Ribose 5 Phosphate is used to make nucleotides.

Question 2

What are the overall steps in the pentose phosphate pathway?

Answer 2

Glucose 6 Phosphate goes through the oxidative chain to become Ribulose 5 Phosphate, releasing a CO2 and an NADPH. Called pentose phosphate pathway because Ribulose 5 phosphate and ribose 5 phosphate are pentose sugars.
The non oxidative chain takes you from fructose 6 phosphate to ribose 5 phosphate without generating NADPH.
Ribulose 5 phosphate can be converted into ribose 5 phosphaate. Ribose 5 phosphate is used for nucleotide base creation. NADPH is used for fatty acid synthesis, alcohol detoxification, etc.

Question 3

What is glycogen?

Answer 3

Glycogen is a clever way to store glucose in the body’s cells. Glycogen allows for controlled release of glucose when called upon.

Question 4

Why do we need glycogen?

Answer 4

Glycogen keeps us alive and functional after the glycolysis from meals has started to die down.

Question 5

What signals regulate glycogen synthesis and breakdown?

Answer 5

Glycogen synthesis is stimulated by the presence of insulin in the body. Breakdown is stimulated by the presence of glucagon (at times of starvation).

Question 6

What signals regulate the pentose phosphate pathway?

Answer 6

NADPH is the major negative inhibtor (more means stop making some)
Phase II of pentose phosphate pathway is hindered by the presence of passengers/strangers you encounter.

Question 7

What are alpha 1-4 linkages in glycogen?

Answer 7

direct linkages along a branch

Question 8

What are alpha 1-6 linkages in glycogen?

Answer 8

branching linkages, they take glycogen residues from a 12-long chain (or multiple of 12) and break it off to form a branch.

Question 9

How many glucose molecules sit between branches?

Answer 9

12!

Question 10

What are the non-reducing ends in glycogen?

Answer 10

These are ends of glycogen where glucose can still be added.

Question 11

Where does glycogen synthesis and breakdown occur?

Answer 11

In muscle and the liver. Glycogen breakdown in the muscle is used for energy (glucose to glycolysis to lactate) Glycogen is stored in the liver to support the needs of the brain and RBCs after a period post-meal

Question 12

How is glycogen broken down?

Answer 12

Glycogen is broken down by glycogen phosphorylase BUT!!! glycogen phosphorylase can’t break down the last 4 residues near a alpha 1-6 branch linkage. Transferase is used to add 3 of the four linkages to the longer chain, and the glycogen breakdown can then occur as normal through glycogen phosphorylase. Then ,alpha 1-6 gucosidase removes the last glucose molecule (which had been 1-6 bound to the longer chain)

Question 13

What is NADPH used for?

Answer 13

Alcohol detoxification, fatty acid biosynthesis

Question 14

What is the starting molecule for the oxidative chain of the pentose phosphate pathway?

Answer 14

Glucose 6 Phosphate

Question 15

What is the starting molecule for the non-oxidative chain of the pentose phosphate pathway?

Answer 15

Fructose 6 Phosphate

Question 16

How is excess glucose stored in the body?

Answer 16

In glycogen! Glycogen granules exist in the cytoplasm, large globs with tens of thousands of glucose units.

Question 17

How does glycogen elongation occur?

Answer 17

You start with a glycogenin core molecule (glycogen needs something to add onto), to which 4 UDP glucose substrates are added. From there glycogen synthase is able to add UDP-glucose to the chain. After at least twelve glucose molecules, an alpha 1-6 linkage is made to create a new branch. The glycogen branching enzyme takes six or seven glucose residues and pulls them onto the new branch. Glycogen synthesis requires energy.

Question 18

What are the specific steps in glycogen elongation?

Answer 18

5 steps!

1: Glucose 6 phosphate is turned into glucose 1 phosphate by phosphoglucomutase
2: Glucose 1-phosphate donates glucose to uridine diphosphate (UDP) to form UDP-glucose through the enzyme UDP-glucose pyrophosphorylase
3: Glycogenin core adds 4 UDP-glucose substrates
4: Glycogen synthase is then able to add UDP-glucose through alpha 1-4 linkages
5: After at least 11 glucose residues a branching enzyme takes six or seven glucose residues and forms an alpha 1-6 linkage. from this branch additional glycogen synthesis can occur.

Question 19

What is glycogen used for?

Answer 19

Glycogen serves as a fuel source in muscles and other cells that require a lot of fuel. In the liver it is used a source of glucose for the RBCs and the brain.

Question 20

What are the overview steps for glycogen breakdown?

Answer 20

Glycogen –> glucose 1-phosphate –> glucose 6 phosphate –> glucose

Question 21

Does glycogen synthesis and/or glycogen breakdown require energy?

Answer 21

Glycogen synthesis takes energy, glycogen breakdown does not!

Question 22

What step in glycogen synthesis requires energy?

Answer 22

Going from glucose 1-phosphate to UDP-glucose (UTP –> UDP)

Question 23

What are the steps in glycogen degradation?

Answer 23

4 steps:

1: phosphorylated glycogen phosphorylase cleaves the alpha 1-4 linkages between adjacent glucose residues, releasing a glucose-1 phosphate molecule. This continues until glycogen phosphorylase reaches the 4 last residues on a branch (the alpha 1-6 bond prevents further progress by glycogen phosphorylase).
2: amylo-4,6-transferase removes the outer 3 glucose residues from the branch and puts them on the end of a nearby chain.
3: alpha 1,6 glucosidase (debranching enzyme) cleaves the alpha 1-6 branched bond.
4: Glucose 1 phosphate is converted to glucose 6 phosphate by phosphoglucomutase.

Question 24

What is glycogen phosphorylase?

Answer 24

Key enzyme in breakdown of glycogen. It phosphorylates glycogen end residues and allows glucose 1-phosphate to pop off.

Question 25

Why can only the liver transport glucose out of a cell?

Answer 25

Glucose is turned into g 6-p when it’s brought into cells. The liver is the only place in the body that has glucose 6-phosphatase, which can cleave the phosphate and allow glucose to be transported out of the cell.

Question 26

What hormones regulate glycogen breakdown?

Answer 26

glucagon and epinephrine (you want to break down glycogen when you’re lacking glucose. glucagon is released in fasting states). glucagon regulates glycogen breakdown in the liver. epinephrine regulates glycogen breakdown in muscles.

Question 27

How do glucagon and epinephrine regulate glycogen breakdown?

Answer 27

Glucagon binds to a GPCR, which phosphorylates G protein alpha subunit. The G protein subunit detaches from beta/gamma subunits and binds to adenylate cyclase, which converts ATP to cAMP. cAMP binds to the regulatory subunits blocking Protein Kinase A and allows protein Kinase A to become active. PKA then goes on to phosphorylate phosphorylase kinase, another enzyme. Phosphorylase kinase becomes active, and activates glycogen phosphorylase A. This is the phosphorylase that separates glucose 1 phosphate molecules from the glycogen strand. Epinephrine does basically the same thing.

Question 28

Where specifically within the liver does the conversion of glucose 6-p to glucose (the last step in glycogen breakdown) occur?

Answer 28

In/across the Endoplasmic Reticulum

Question 29

What is glycogenin?

Answer 29

Glycogenin is a “primer” for glycogen chains. It is the core molecule that the other UDP-glucose molecules are able to add to.

Question 30

What hormones/environments regulate glycogen synthesis? How?

Answer 30

High ATP environments encourage glycogen synthesis. Presence of insulin stimulates glycogen synthesis. Insulin activates phosphatase 1 and deactivates glycogen synthase kinase. Glycogen synthase is active in the non-phosphorylated form, so insulin is keeping it from becoming inactive.

Question 31

Do insulin and glucagon only stimulate or inhibit in the glycogen pathways?

Answer 31

Both! They’re doubly effective, because they’ll activate one enzyme and inhibit the other. Glucagon will activate glycogen synthase kinase, which inhibits glycogen synthase. Glucagon will also inhibit phosphatase 1 (which would promote glycogen synthase). Insulin does the opposite.

Question 32

What are some glycogen storage diseases? What are their symptoms?

Answer 32

You wouldn’t be able to store energy, so you would be tired. Your brain would have dysfunction if it got severe, because you wouldn’t have enough glucose? Von Gierke disease has a defect in glucose 6 phosphatase, which means glucose can’t leave the liver. So the liver gets massive, and you don’t have enough energy.
Glycogen storage disease (type III) has a defect in the debranching enzyme, which means you have a bunch of short branches. It’s harder to release glucose from short branches. Type III is not as bad as Von Gierke but has similar symptoms.

Question 33

How is alcohol metabolized?

Answer 33

Two pathways: microsomal ethanol oxidizing system (MEOS) and alcohol dehydrogenase. MEOS is less common but is used in situations with high alcohol concentrations. Alcohol dehydrogenase turns ethanol into acetaldehyde and then into acetate. This uses 2 NAD+ –> NADH. Acetaldehyde is the toxic molecule that has you feeling gross after drinking. The MEOS system uses NADPH (got from pentose phosphate pathway. Enzymes in ER (cytochrome p450!!) turn ethanol into acetaldehyde. This pathway is only used at really high concentrations of ethanol, and results in the production of free radicals, which can do a lot of damage. The most common enzyme used is CYP2E1

Question 34

Where do the long term bad side effects of alcoholism come from?

Answer 34

Having too much NADH compared to NAD+. NADH is generated by alcohol dehydrogenase. This inhibits fatty acid oxidation (needs NAD+). Fat accumulates in the liver (fatty acid disease). Acetyl CoA is shifted away from the TCA cycle, produces ketones but causes ketoacidosis because ketones are acidic. Lactate dehydrogenase is shifted towards making lactate, and uric acid isn’t gotten rid of. Uric acid crystals get stuck in the body and cause gout, or tons of pain whenever someone tries to move.

Question 35

What is alcohol dehydrogenase?

Answer 35

Low kM for ethanol (high binding affinity) and is active at low ethanol concentrations.

Question 36

What is acetaldehyde dehydrogenase?

Answer 36

It’s used to go from acetaldehyde to acetate in the metabolism of alcohol!

Question 37

What does the ALDH2K2 mutation do to acetaldehyde dehydrogenase?

Answer 37

Protects against alcoholism! Acetaldehyde doesn’t bind well to acetaldehyde (high Km) and doesn’t do much (low Vmax) so you feel sicker sooner from drinking (concentrations of acetaldehyde are higher)