WEEK 3 (Glycogen Metabolism) Flashcards
What is the biological importance of Glycogen?
Used as a CARBOHYDRATE RESERVE where glucose phosphates and glucose can be released when needed
Why is Glycogen more useful than Glucose storage?
High concentrations of Glucose within cells would make them STRONGLY HYPOTONIC and would cause an INFLUX OF WATER but insoluble glycogen has a LOW OSMOTIC ACTIVITY
Describe muscle and liver glycogen
- Can store up to 450g of glycogen (1/3 in Liver & 2/3 in Muscle)
- MUSCLE GLYCOGEN provides a readily available source of GLUCOSE-1-PHOSPHATE for GLYCOLYSIS
- LIVER GLYCOGEN functions as a reserve to maintain the blood glucose concentration in the FASTING STATE
Describe the structure of Glycogen
- Branched-chain polysaccharide made from D-GLUCOSE
- Primary glycosidic bond is 1,4 LINKAGE
- After an average of 8-10 GLUCOSYL RESIDUES, there is a branch containing 1,6 LINKAGE
Describe the Glycogen store fluctuation
- Liver glycogen stores increase during the WELL-FED STATE and are DEPLETED during a FAST
- Muscle glycogen is not affected by short periods of fasting (a few days) and is only moderately decreased in prolonged fasting (weeks)
Where does Glycogen synthesis take place?
In the cytosol
What are the properties of Glycogen Synthesis?
- Process occurs in Cytosol
- Requires energy supplied by ATP & UTP
What does Glycogen synthase make?
Alpha (1,4) linkages
What does the Branching enzyme do?
Removes a chain of 6 to 8 GLUCOSYL RESIDUES from glycogen chain & attaches it to a NON-TERMINAL GLUCOSYL RESIDUE by an alpha (1,6) linkage
What are the 4 main steps in Glycogen synthesis?
1) Attaching URIDINE DIPHOSPHATE (UDP) to GLUCOSE
2) Attaching GLUCOSE to GLYCOGENIN which serves as a PRIMER
3) Adding more glucose to the primer
4) Adding branches to the glycogen molecule
What are the enzymes that are used in the conversion of Glucose to Branched Glycogen?
- Hexokinase/Glucokinase
- Phosphoglucomutase
- UDP-Glucose Pyrophosphorylase
- Glycogen Synthase
- Branching Enzyme
Describe the steps of Glycogenesis
1) PHOSPHOGLUCOMUTASE moves the phosphate from the 6th carbon of Glucose to the 1st making GLUCOSE-1-PHOSPHATE. UDP-GLUCOSE PYROPHOSPHORYLASE cuts 2 phosphates off UTP which provides ENERGY for this reaction. UDP-Glucose is formed.
2) GLYCOGEN SYNTHASE catalyses the attachment of the Glucose part of the UDP-Glucose molecule to another glucose residue at the END of the GLYCOGEN BRANCH forming an ALPHA 1,4 GLYCOSIDIC BOND
3) BRANCHING ENZYME shortens the chain and attaches the cut chain to the side of another LINEAR GLYCOGEN CHAIN by creating an ALPHA 1,6 GLYCOSIDIC BOND
4) GLYCOGEN SYNTHASE elongates the chain again creating a BRANCHED GLYCOGEN TREE storing energy
Why is Glycogenin necessary in Glycogen synthesis?
Glycogen synthesis can only occur in an elongating glycogen chain that is already 4 glucose molecules long. Glycogenin attaches 4 glucose molecules to itself mimicking the first step of Glycogen synthesis.
Which part of the Glycogen molecule does Glycogenolysis begin?
The branches
Describe the steps of Glycogenolysis
1) GLYCOGEN PHOSPHORYLASE cleaves ALPHA 1,4 BONDS between individual glucose residues & catalyses the transfer of PHOSPHATE GROUP to the FREE GLUCOSE forming GLUCOSE-1-PHOSPHATE molecules which are released ONE AT A TIME (continues until 4 Glucose are left)
2) DEBRANCHING ENZYME cuts off branches. 4-ALPHA-GLUCANOTRANSFERASE transfers 3/4 glucose molecules off the branch and reattaches to the LINEAR GLYCOGEN CHAIN, extending it. ALPHA 1,6 GLYCOSIDASE cleaves the ALPHA 1,6 BOND which releases a FREE GLUCOSE
3) PHOSPHOGLUCOSEMUTASE converts GLUCOSE-1-PHOSPHATE to GLUCOSE-6-PHOSPHATE
5) IN LIVER, GLUCOSE-6-PHOSPHATASE removes phosphate and releases free glucose into the BLOODSTREAM (increasing blood glucose concentration). IN MUSCLES, NO GLUCOSE-6-PHOSPHATASE so sends Glucose-6-Phosphate into GLYCOLYSIS PATHWAYS to be used for ENERGY
What are the two catalytic sites in a single polypeptide chain?
- 4-ALPHA-GLUCANOTRANSFERASE which transfers a trisaccharide unit from one branch to another
- ALPHA 1,6 GLUCOSIDASE which catalyses the hydrolysis of the 1,6 GLYCOSIDE BOND to liberate free glucose
A small amount of glycogen is continuously degraded by which lysosomal enzyme?
Alpha 1,4 Glucosidase (acid maltase)
What does the deficiency of Alpha 1,4 Glucosidase cause?
GLYCOGEN STORAGE DISEASE TYPE II: POMPE DISEASE
Disease causes accumulation of glycogen in vacuoles in the lysosomes
Why does the Liver contain Glucose-6-Phosphatase and the Muscle does not?
The LIVER releases glucose to the BLOOD to be taken up by BRAIN and ACTIVE MUSCLE & regulates BLOOD GLUCOSE LEVELS. The MUSCLE retains glucose-6-phosphate to be used for ENERGY. Phosphorylated glucose is not transported out of muscle cells.
What is the difference between Glycogen Synthase and Glycogen Phosphorylase?
GLYCOGEN SYNTHASE is active without phosphate whereas GLYCOGEN PHOSPHORYLASE is active with phosphate
Describe the Hormonal Regulation (increase in glucose)
1) Blood glucose level increases and Insulin is released from the pancreas.
2) Insulin binds to a TYROSINE KINASE RECEPTOR on the cell surface membrane which ACTIVATES PROTEIN PHOSPHATASE which removes phosphates from GLYCOGEN SYNTHASE (activating it) and GLYCOGEN PHOSPHORYLASE (deactivating it)
3) Promotes glycogen synthesis and inhibits glycogen breakdown
Describe the Hormonal Regulation (decrease in glucose)
1) Blood glucose level decreases and Glucagon in LIVER CELLS bind to G-PROTEIN COUPLED RECEPTOR on the cell surface membrane
2) Activates ADENYLYL CYCLASE which converts ATP to cAMP. cAMP activates PROTEIN KINASE A which adds phosphate to GLYCOGEN PHOSPHORYLASE (activating it) and GLYCOGEN SYNTHASE (deactivating it)
3) Promotes glycogen breakdown and inhibits glycogen synthesis
How does Epinephrine affect blood glucose concentration?
Increases it since the binding to a B-receptor (liver and muscle) and a-receptor (liver) provides phosphate to Glycogen Phosphorylase (activating it) and Glycogen Synthase (deactivating it) -> Promotes glycogen breakdown and inhibits glycogen synthesis
Describe what happens in the well-fed state
In the well-fed state, GLYCOGEN SYNTHASE B in both LIVER and MUSCLE is ALLOSTERICALLY ACTIVATED by GLUCOSE-6-PHOSPHATE which is present in elevated concentrations. In contrast, GLYCOGEN PHOSPHORYLASE A is ALLOSTERICALLY INHIBITED by GLUCOSE-6-PHOSPHATE and ATP
What is the difference between Type Ia and Type Ib Von Gierke Disease?
- TYPE IA VON GIERKE DISEASE = GLUCOSE-6-PHOSPHATASE DEFICIENCY
- TYPE IB VON GIERKE DISEASE = GLUCOSE-6-PHOSPHATE TRANSLOCASE DEFICIENCY
Describe Type Ia Von Gierke Disease
- GENE DEFECT = G6PC GENE ON CHROMOSOME 17q
- DEFICIENT ENZYME = GLUCOSE-6-PHOSPHATASE
- ROLE OF THE ENZYME = Hydrolysis of Glucose-6-Phosphate to glucose and inorganic phosphate (inhibits final step of Gluconeogenesis)
Describe Type Ib Von Gierke Disease
- GENE DEFECT = SLC37A4 GENE ON CHROMOSOME 11q
- DEFICIENT ENZYME = GLUCOSE-6-PHOSPHATE TRANSLOCASE
- ROLE OF THE ENZYME = Transport of Glucose-6-Phosphate into the Endoplasmic Reticulum where it is hydrolysed by Glucose-6-Phosphatase
What are the symptoms of both Type Ia and Type Ib Von Gierke Disease?
- Renomegaly & Hepatomegaly
- Severe fasting hypoglycaemia
- Progressive renal disease
- Severe hyperlipidemia (doll-like faces)
- Hyperuricemia
- Lactic acidosis
- Anemia
- Failure to thrive
- Dysfunctional Glycogenolysis and Gluconeogenesis
Describe Type II Glycogen Storage Disease (Pompe Disease)
- GENE DEFECT = GAA GENE ON CHROMOSOME 17q
- DEFICIENT ENZYME = LYSOSOMAL ACID MALTASE DEFICIENCY
- ROLE OF ENZYME = Glycogenolysis & Hydrolysed a-1,4 and a-1,6 linkages in the acidic environment of the lysosome
- EXPLANATION = Deficiency of Lysosomal acid maltase causes glycogen to accumulate in lysosomes of SKELETAL, SMOOTH & CARDIAC MUSCLE CELLS -> can’t degrade WASTE MATERIAL which ACCUMULATES in CYTOPLASM & IMPAIRS MUSCLE CONTRACTION -> Over time the GLYCOGEN ACCUMULATION leads to LYSIS of LYSOSOMES & DESTROYS WHOLE CELL
What is the treatment for Von Gierke Disease?
Nocturnal gastric infusions of glucose or regular administration of uncooked cornstarch
What are the Symptoms of Type II Glycogen Storage Disease (Pompe Disease)?
- CARDIOMEGALY or HYPERTROPHIC CARDIOMYOPATHY (heart cannot pump effectively)
- Macroglossia
- Failure to thrive
- Difficulty breathing/Respiratory failure
- Intracranial aneurysms
What is the diagnosis and treatment of Type II (Pompe disease)?
DIAGNOSIS
- GENETIC TESTING (looking for mutations in ACID MALTASE GENE)
- ADDITIONAL TESTS (increased blood levels of CREATINE KINASE since normally found in muscle cells but leaks into blood when destroyed & MUSCLE BIOPSY w/ PERIODIC ACID SCHIFF STAIN identifying GLYCOGEN ACCUMULATION in LYSOSOMAL VESICLES)
TREATMENT
- Enzyme replacement therapy
What are the Six types of Glycogen Storage Diseases?
- TYPE 1A & TYPE 1B (Von Gierke Disease)
- TYPE 2 (Pompe Disease)
- TYPE 3 (Cori Disease)
- TYPE 4 (Andersen Disease)
- TYPE 5 (McArdle Disease)
- TYPE 6 (Hers Disease)
Describe Type III (Cori Disease)
- GENE DEFECT = AGL GENE ON CHROMOSOME 1p
- DEFICIENT ENZYME = GLYCOGEN DEBRANCHING ENZYME
- ROLE OF THE ENZYME = GLYCOGENOLYSIS
SYMPTOMS
- Hypoglycaemia (Liver is unable to release Glucose from Glycogen into bloodstream)
- Muscle weakness/Cramps
- Cirrhosis
- Hyperlipidemia
- Buildup of Limit Dextrins
- Blood lactate levels are normal
- Hepatomegaly
- Cardiomepathy
Describe Type IV (Andersen Disease)
- GENE DEFECT = GBE1 GENE ON CHROMOSOME 3p
- DEFICIENT ENZYME = GLYCOGEN BRANCHING ENZYME
- ROLE OF THE ENZYME = GLYCOGENESIS
SYMPTOMS
- SYMPTOMS IN EARLY INFANCY = Foetal akinesia sequence, Failure to thrive, Hepatosplenomegaly & Cirrhosis)
- Proximal myopathy
- Cardiomyopathy & Hypotonia
- Peripheral neuropathy
- LATE SYMPTOM = hypoglycaemia
Describe Type V (Mcardle Disease)
- GENE DEFECT = PYGM GENE ON CHROMOSOME 11q
- DEFICIENT ENZYME = MYOPHOSPHORYLASE
- ROLE OF THE ENZYME = Glycogenolysis (breaks down Glycogen into Glucose-1-Phosphate to obtain glucose)
- EXPLANATION = Muscle cells CAN’T BREAK DOWN GLYCOGEN into Glucose-1-Phosphate to OBTAIN GLUCOSE so cells won’t be able to USE GLYCOGEN for energy especially during exercise -> GLYCOGEN ACCUMULATES in MUSCLE CELLS which die (RHABDOMYOLYSIS) -> CELLULAR CONTENTS RELEASED into BLOODSTREAM ELECTROLYTES -> HYPERKALEMIA & HYPERPHOSPHATEMIA
Describe Type V (Mcardle Disease)
- GENE DEFECT = PYGM GENE ON CHROMOSOME 11q
- DEFICIENT ENZYME = MYOPHOSPHORYLASE
- ROLE OF THE ENZYME = Glycogenolysis (breaks down Glycogen into Glucose-1-Phosphate to obtain glucose)
- EXPLANATION = Muscle cells CAN’T BREAK DOWN GLYCOGEN into Glucose-1-Phosphate to OBTAIN GLUCOSE so cells won’t be able to USE GLYCOGEN for energy especially during exercise -> GLYCOGEN ACCUMULATES in MUSCLE CELLS which die (RHABDOMYOLYSIS) -> CELLULAR CONTENTS RELEASED into BLOODSTREAM ELECTROLYTES -> HYPERKALEMIA & HYPERPHOSPHATEMIA
SYMPTOMS
- Muscle Weakness
- Exercise intolerance
- Rhabdomyolysis & Myoglobinuria
- Cardiac Arrythmias (due to electrolyte imbalance)
- Normal serum glucose levels
What is the “Second wind phenomenon”?
Happens in Type V (McArdle Disease) and is when symptoms of muscle fatigue disappear after a period of activity because of increased muscular blood flow
Describe Type VI (Hers Disease)
- GENE DEFECT = PYGL GENE ON CHROMOSOME 14q
- DEFICIENT ENZYME = LIVER PHOSPHORYLASE
- ROLE OF THE ENZYME = GLYCOGENOLYSIS
SYMPTOMS
- Hepatomegaly
- Fasting hypoglycemia & ketosis
- Hyperlipidemia
