PHR912: Block 2: Carbohydrate Metabolism 4

Structure of Glycogen:

Branched polysaccharide, consisting of glucose units

Storage form of glucose

What kind of linkages are present in glycogen

alpha(1→4)

alpha (1→6) linkages at the branches

Every 8-14 residues

Anomeric carbon of glycogen:

Only one free anomeric carbon at the reducing end of glycogen

Due to the highly branched structure of glycogen:

Allowing for quick (parallel) access for biosynthesis or degradation

Where do glycogen molecules cluster together:

Tissues: Glycogen molecules

How does glycogen differ from amylopectin?

Glycogen is much more branched.

Where are the branch points in glycogen?

every 8-12 glucose units

Most cells only have how much of glycogen stored?

Small amounts

Where are the primary location of glycogen storage?

Liver and muscle

Glycogen storage can be compromised through:

Glycogen storage disease

What does liver glycogen do?

Used to maintain blood glucose levels (glucose buffering system)

Important fuel during anaerobic glycolysis where large amounts of glucose are consumed

Glycogen breakdown:

Glycogenolysis

How many enzymes are in glycogen breakdown?

Glycogen phosphorylase 

Glycogen debranching enzyme

Phosphoglucomutase

What is the end product of glycogen breakdown?

Glucose-6-phosphate

Why is phosphoglumutase reversible?

To allow the levels of glucose-1-phosphate and glucose 6-phosphate to easily altered in the cell.

Glycogen Phosphorylase:

Catalyzes glycogen phosphoryolysis to yield glucose-1-phosphate

Glycogen phosphorolysis definition:

Bond cleavage by subsitiution of a phosphate group

What is glycogen phosphorylase end product?

Glucose-1-phosphate

Glycogen phosphorylase removes:

glycosyl units one at a time from the non-reducing end of chain

Why can glycogen phosphorylase not function on short chains:

Cannot function on short chains of 4 residues of an alpha (1→6) branch point due to steric hindrance

How many forms does glycogen phosphorylase have:

2

Phosphorylase a

Phosphorylase b

Phosphorylase a:

Active glycogen phosphorylase

Phosphorylated at Ser 14; dimer of 2 identical 842-residue subunits

Phosphorylase b:

Inactive glycogen phosphorylase

“Blocked” dephosphorylated at Ser-14

What is the rate limiting step of glycogen breakdown?

Glycogen phosphorylase

Glycogen phosphorylase phosphorylation/dephosphorylation is controlled by what?

Glucagon/Insulin

Activators of glycogen phosphorylase: Alloseric

AMP

Allosteric inhibitors of glycogen phosphorylase:

ATP

G6P

glucose

Because you have enough glucose, you dont need to break down more.

Glycogen degradation by glycogen phosphorylase:

Only non reducing end residues are cleaved off, one by one

What bonds do glycogen phosphorylase only act on?

Alpha-glycosidic bonds

What type of reaction is glycogen phosphorylase?

SN-1

What assists glycogen phosphorylase?

Pryidoxalphosphate

Glycogen Debreanching Enzyme:

Removes glycogen’s branches through trisaccharide transfer and hydrolysis of the remaining residue to yeild glucose

What does glycogen debranching enzyme also take care of?

Last 4 residues at branch points

2 catalytic activities of glycogen debrancing enzyme:

alpha (1→4) transglycosylase

alpha (1→6) glucosidase

Alpha (1→4) transglycosylase activity:

Transfers an alpha-(1→4) linked triasccharide units to a 4-position nonreducing end of another branch

Alpha- (1→6) glucosidase activity:

Hydrolyses the remaining alpha (1→6) linked glucose, releasing one free glucose unit per branch

Phosphoglucomutase:

Converts glucose-1-phosphate to glucose-6-phosphate

What reaction does phosphoglucomutase catalyze:

Glucose-1-phosphate → Glucose-6-phosphate

What is the intermediate for phosphoglucomutase?

Glucose-1,6-bisphoshate

First step of phosphoglucomutase:

A phosphoryl group is transferred from the active phosphoenzyme to G1P, forming glucose-1,6-bisphosphate (G1,6P)

Second step of phosphoglucomutase:

G1,6P rephosphorylates the enzyme by sactificing its phosphate at the 1-position, yeilding G6P

Where is glucose-6-phosphatase?

Only in the liver

What does glucose-6-phosphatase do?

Converts glucose-6-phosphate to glucose

Glucose-6-phosphatase equation:

G6P + H2O → Glucose + pi

Liver acts as the what:

Glucose buffering system

Glucose-6-Phosphatase allows the liver to do what?

Release glucose into the blood

Glycogen Phosphorylase (GP) is all below EXCEPT

GP’s b form is phosphorylated at Ser-14

Which of the following statements about the debranching enzyme is WRONG?

It moves 6-8 glucose residues from one glycogen branch to another

Where can you expect to find the enzyme catalyzing this shown reaction?

Liver

Glycogen biosynthesis (synthesis) is NOT the what?

Reverse of the breakdown pathway

Enzymes of Glycogen Biosynthesis:

• UDP-Glucose pyrophosphorylase

• Glycogen synthase

• Glycogen branching enzyme

UDP-glucose pyrophosphorylase:

Activates glucose

G1P + UTP → UDP-Glucose + PPi

Glycogen synthase:

Elongates glycogen chains at nonreducing ends

UDP-glucose + glycogen (n residues) → Glycogen (n+1 residues) + UDP

Glycogen branching enzyme:

Makes branches by transferring 6-8 residue sgments form the end of one chain to the 6-OH group of  a glucose residue on the same or another glycogen chain

UDP-glucose pyrophosphorylase covercomes the irreverisble step of?

Glycogen phosphorylase

UDP-glucose formation is: UDP glucose pyrophosphorylase

A phosphoanhydride exchange reaction

What is yielded during UDP-glucose pyrophosphorylase?

A pyrophosphate for extra energy

What does UDP-glucose pryophosphorylase produce?

UDP-glucose

UDP-glucose may leave the pathway for:

Glycogen synthesis and be used for the addition of carbohydrates to other compounds (ex: glycopeptides)

Glycogen Synthease:

The glycosyl unit of UDP-glucose is transferred to the 4-OH group of a nonreducing end of glycogen

First step of Glycogen Synthase:

The UDP activator is removed leaving an electron-poor oxonium ion intermediate (UDP is a good leaving group)

Second step of glycogen synthase:

Oxonium ion intermediate is attacked by the 4-OH group of a glucose (at the end of nonreducing glycogen chain) under release of one H+ ion

Formation of glycogen is what kind of reaction?

Sn1

Glycogen Branching Enzyme

Provides the branches at 6-positions of glucose residues because glycogen synthase can only generate alpha(1 →4) linkages.

Other names for glycogen branching enzyme:

Amylo-1,4 → 1,6)- transglycosylase

Amylo-4:6-transferase

What does the glycogen branching enzyme cleave?

The 6-8 residues from a growing chain once it has reached 11-13 residues and attaches them alpha(1→6) to a glucose of the same or another chain to form a branch

How far must branch points be apart from one another?

At least 4 residues

Purpose of glycogen branching enzyme:

To maintain the highly branched structure of glycogen and allow branching for rapid growth.

Most of the synthesis consists of addition of glucose units to what?

Existing chain (glycogen primer)

The reducing end of glycogen is attached to what?

The protein glycogenin

Synthesis of glycogen primer 1st step:

Glycogenenin is glycosylated by a tyrosine glycosyltransferase at Tyr-194

Second step of synthesis of glycogen primer:

Glycogenin autocatalytically attaches up to 7 additional glucose units using UDP-glucose building blocks, making the chain long enough to serve as substrate for glycogen synthease

The glycogen branching enzyme is/does all below except?

Remove branches from glycogen

Glycogenin is/does all below except?

Is a unique enzyme of gluconeogenesis

The following reactions are/do all listed EXCEPT?

G1P + UTP → UDP-Glucose + 2Pi

The reactions are necessary in context with the glycogen breakdown

Allosteric: If ATP and G6P are high:

Glycogen biosnthesis is on: activation of glycogen synthase

Glycogen breakdown is off: Inhibition of glycogen phosphorylase

Allosteric: If AMP is high (ATP and G6P is low)

Glycogen degradation is on: Stimulation of glycogen phosphorylase

Glycogen synthesis is off: Inhibition of glycogen synthase

Hormonal: Insulin always cuases what?

Dephoshorylation

Hormonal: Glucagon always causes what?

Phosphorylation

Hormonal: Epinephrine stimulates what?

Muscles and liver

Glucagon only affects what?

Liver

Ca+2 also can stimulate what:

Muscles (not liver) to undergo glycogen breakdown

Which of the following statements concerning the regulation of the glycogen metabolism is WRONG?

AMP activates glycogen synthase

How could hereditary glycogen storage diseases be handled or treated in the future?

Not at all

Avoiding certain activties

Changing eating habits

Biologics → Enzyme replacement

Surgically

How is Anderson’s treated?

Not at all

How is McArdles treated?

Avoid certain activities

How is Hers’ and Cori’s treated?

Changing eating habits

How is Pompe’s treated?

Biologics → Enzyme replacement

How is von Gierke’s treated?

Surgically and drugs that inhibit glucose-uptake by the liver over surgical transposition of the portal vein to liver transplantation

Von Gierke’s Disease

Deficiency of liver glucose-6-phosphatase

Effects the ability to maintain blood glucose because glucose cannot be dephosphorylated

Effects of Von Gierke’s

Enlarged liver, hypoglycemia, failure to thrive

Pompe’s Disease:

Deficiency of alpha-1,4-glucosidase

Most devastating of the glycogen storage diseases

Large accumulation of glycogen in the lysocsomes of all cells

Expectancies of Pompe’s Disease:

Death by cardiorespiratory failure usually before reaching 1.

Cori’s Disease:

Incomplete glycogen degradation due to absence of debranching enzyme

Glycogen with abnormal structure accumulates in muscle and liver

Symptoms often disappear at puberty

Cori’s disease treatment and symptoms

Non-severe hypoglycemia

Can be treated with a high protein diet/frequent eating

Andersen’s Disease

Branching enzyme of glycogen biosynthetic pathway is missing

One of most severe

Liver glycogen exists in abnormal, long, unbranched amylose-type chains

Expenctancy of Andersen’s Disease

Victims seldom survive past 4 due to liver dysfunction

Liver dysfunction may be caused by an immune reaction to the abnormal glycogen

McArdle’s Disease

Deficiency of muscle glycogen phosphorylase

Painful muscle cramps and unusual fatigue during exercise

Symptoms do not usually appear before early adulthood

Liver glycogen phosphorylase exists in normal amounts

How to prevent McArdle’s disease?

Prevented by avoiding strenuous exercise

Hers’ Disease:

Deficiency of liver glycogen phosphorylase

Hypoglycemia, Hepatomegaly from inability of liver glycogen phosphorylase to respond to need for glucose

Not too severe