G - Glycogen

Glycogen Phosphorylase

****REQUIRES: PLP Cofactor**** cleaves Glucose residues from glycogen chains by breaking α1-4 bonds ACTIVATED by: Glucagon, AMP (muscle) INHIBITED by: Insulin, Epinepherine (liver only), ATP (muscle), G6P (muscle)

Glycogen Synthase

Adds Glucose from UDP-Glucose to growing Glycogen chain ACTIVATED by: Insulin, Cortisol INHIBITED by: Glucagon (liver), Epinepherine (muscle)

Glycogenin

Autoenzyme (acts on itself) Adds Glucose to itself from UDP-Glucose to create a primer for Glycogen Synthase Becomes the core of the glycogen granule

Phosphoglucomutase

G6P --> G1P G1P --> G6P

Structure of the Glycogen Particle

Glygogenin primer at core Several tiers of branches Tree-like structure

PLP

Vitamin B6 Required for Glycogen Phosphorylase (note - they both contain a P!) PLP GP Please Let Pretty Girls have Glytter Pheet (feet)

Glycogen

- Polymer of glucose - primary storage form for glucose in humans. - In the fed state, glycogen makes up 8-10% of the wet weight of the liver, and 2% of skeletal muscle. - Primary function of liver glycogen is to provide energy for the CNS during fasting. - Liver glycogen is ~50% depleted after an overnight fast and ~85% depleted after a 24 hr fast. - Muscle glycogen serves as a source of energy for muscular contraction.

Glycogen Breakdown (Basic Steps)

1) Shortening of Chains 2) Removal of Branches 3) Conversion of G1P --> G6P 4) Lysosomal Degredation of Glycogen

Glycogen Syntehesis (Basic Steps)

1) Synthesis of UDP-Glucose (Uridine Diphosphate Glucose) 2) Synthesis of Primer to initiate Glycogen Synthesis 3) Elongation of Glycogen Chains by Glycogen Synthase 4) Synthesis of Branches

Synthesis of Glycogen Branches

1) When chain is at least 11 residues long... 2) Glycogen Branching enzyme removes the terminal 6-8 Glucose molecules (branch chain) from the chain. (breaks α1-4 bond) 3) It then attaches the branch chain to a glucose residue closer to the beginning of the chain by FORMING an α1-6 bond! When the 2 new branches (original chain and new branch chain) grow to 11 residues long, this cycle can repeat to make additional branches. This enzyme is a 4:6 Transferase (breaks α1-4, makes α1-6)

Limiting Dextrin

A glycogen molecule that cannot be further broken down by Glycogen Phosphorylase (also used to refer to sugar molecules that cannot be further broken down by digestive enzymes prior to absorption)

Phosphorylation Cascades

Always result in Signal Amplification Basic steps are: 1) Activates Adenylate Cyclase (AC) 2) AC activates Cyclic AMP 3) cAMP activates Kinase 4) Kinase phosphorylates a bunch of stuff

Glycogen Branches

Branches are located ~8 residues apart Form a tree-like structure Makes Glycogen more soluble Increases number of ends that Glucose can be added to for elongations, accelerating rate of glycogen synthesis Linear Glycogen (amylose) only found in plants

α1-6 Glucosidase

Breaks α1-6 bond of glucose residue at the branch point of a glycogen molecule, releasing the residue as a free glucose

Activation of cAMP Cascade (Liver)

Deactivates Glycogen Synthesis: - Glycogen Synthase is phosphorylated by the cAMP cascade - Phosphorylation of Glycogen Synthase promotes the "b" (less active) conformation. Instead of being converted to glycogen, glucose-1-P in liver may be converted to glucose-6-P, and dephosphorylated for release to the blood.

Removal of Glycogen Branches

Debranching Enzyme (bifunctional enzyme) 1) Removes outer 3-4 glucosyl residues attached to the branch point (breaks α1-4 bond) 2) Transfers these 3-4 residues to the nonreducing end of a glycogen chain (makes α1-4 bond) [This enzyme is a 4:4 Transferase (breaks α1-4 and makes a new α1-4)] 3) Remaining residue at branch point is removed via an α1-6 Glucosidase, releasing a free glucose The glycogen chain is now available to be broken down again by Glycogen Phosphorylase

Tarui's Disease ( Glycogen Storage disease VII)

Deficient Enzyme: Phosphofructokinase of muscle (PFK or PFK1) Very rare in infants Symptoms: Exercise-induced muscle cramps and weakness, myoglobinuria (myoglobin in urine) Treatment: - No specific treatment exists - Avoid high-carbohydrate meals, as they can exacerbate exercise intolerance - Prenatal detection may be possible in families with identifiable mutations.

Glycogen Storage Disease Symtoms (Liver vs Muscle Enzyme Deficiencies)

Enzyme defects in LIVER: a common symptom is hypoglycemia, relating to impaired mobilization of glucose for release to the blood during fasting. Enzyme defects in MUSCLE: weakness & difficulty with exercise result from inability to increase glucose entry into Glycolysis during exercise. Additional symptoms depend on the particular enzyme that is deficient.

Synthesis of UDP-Glucose

G6P--> G1P (Phosphoglucomutase) G1P + UTP ---> UDP Glucose Enzyme: UDP-Glucose Phosphorylase reversible rxn

Glycogen Storage Diseases

Genetic enzyme deficiencies associated with excessive glycogen accumulation within cells. Some enzymes whose deficiency leads to glycogen accumulation are part of the inter-connected pathways shown in pic. Can cause Tarui's Disease (GSD VII) Or von Gierke's Disease

Glucagon and Epinephrine Action

Glucagon (liver) and Epinephrine (muscle) both cause a Phosphorylation Cascade 1) G or E binds and activates Adenylate Cyclase (AC) membrane protein 2) AC converts ATP --> Cyclic AMP 3) cAMP activates Protein Kinase A (PKA) 4) PKA Phosphorylates Phosphorylase Kinase 5a) Phosphorylase Kinase phosphorylates Glycogen Synthase and DEACTIVATES it 5b) Phosphorylase Kinase phosphorylates Glycogen Phosphorylase and ACTIVATES it (phosphorylase b --> phosphorylase a) 6) Glycogen breakdown SUMMARY: Glycagon and Epi cause a cAMP dependent PKA Phosphorylation cascade that adds Pi to a bunch of enzymes resulting in the activation of Glycogen Breakdown

Fate of Excess Glucose in ADIPOSE

Glucose --> DHAP --> Glycerol P --> TAGs

Fate of Excess Glucose in RBC

Glucose --> Pyruvate --> Lactate (for ATP) or --> NADPH (protect from ROS) (Pentose Phosphate Pathway)

Shortening of Glycogen Chains

Glycogen Phosphorylase cleaves α1-4 bonds (starting from the nonreducing end and working inward towards the center of the granule) until only 4 glucose residues remain on the chain before a branch point Resulting structure is called a Limiting Dextrin

Synthesis of Primer to initiate Glycogen Synthesis

Glycogen Synthase can NOT initiate synthesis with only a UDP-G and a free glucose, a primer must be made 1) Fragment of Glycogen can be used as a primer OR 2) Glycogenin (autoenzyme) attaches a Glucose from UDP-G to itself. It does this a few times until the nee Glycogen fragment is long enough for Glycogen Synthase to use. (Glycogenin stays associated with the chain and forms the core of the glycogen granule)

Elongation of Glycogen Chains by Glycogen Synthase

Glycogen Synthase transfers a Glucose from UDP-Glucose to the NONREDUCING end of the growing Glycogen chain (UDP is released and can make a new UTP via Kinase activity) Forms α 1-4 bonds This is the rate limiting, regulated step!!

Glycogen Structure

Glycogen is a polymer of glucose residues linked by a(1->4) glycosidic bonds, mainly a(1->6) glycosidic bonds, at branch points. Glycogen chains & branches are longer than shown. Glucose is stored as glycogen predominantly in liver and muscle cells.

Effect of Cortisol on Liver Glycogen

Increases Glycogen Synthesis (glycogenesis) in the liver Mechanism for this is unknown. (also increases Gluconeogenesis) Net increase in BG

von Gierke's Disease

Most common Glycogen Storage disease Deficiency of glucose-6-phosphatase (G6Pase) Symptoms: Increased glycogen storage in liver & kidney -> Enlargement of these organs Lactic Acidosis Severe hypoglycemia Hypertriglyceridemia Hyperuricemia Treatment: 1) Multiple meals /day to avoid hypoglycemia 2) Feed Glu by nasogastric tube - these techniques keep glucagon low & decreased degradation of glycogen. (Other issues like increased fat synthesis and GOUT also arise).

Muscle vs Liver Glycogen Storage

Muscle --> Own use Liver -->Blood Glucose Stored in as granules, which contain the enzymes for the synthesis and degradation of glucogen in tightly bound form.

Conversion of G1P --> G6P

Phosphoglucomutase converts G1P --> G6P In LIVER G6P is then transferred into the ER by G6P Translocase so that it can be converted to Glucose via the last step of Gluconeogenesis (enzyme: G6Pase) Glucose is then transported to cytosol, and then released into the blood to raise BG In MUSCLE G6P enters Glycolysis

Muscle Metabolism

RESTING muscle: primary fuels are Free Fatty Acids from Adipose tissue and Ketone Bodies from the Liver WORKING muscle: Muscle uses GLUCOSE (from Glycogen) while contracting or exercising (anaerobic Glycolysis)

Unmodified Glycogen Phosphorylase

The relative activity of the un-modified (i.e no P attached) phosphorylase enzyme (given the name phosphorylase-b ) is sufficient to generate enough G1P for entry into Glycolysis for the production of sufficient ATP to maintain the normal resting activity of the cell. (Phosphorylase-a is the more active form) This is true in both liver and muscle cells.

Fate of Excess Glucose in LIVER

goes to 1) Glycogenesis reserve: for maintaining post absorptive BG 2) Glycolysis: after glycogen reserve is full. 3) Triglycerides: TAGs exported to adipose tissue for storage

Fate of Excess Glucose in MUSCLE

goes to: 1) Glucose ---> stored as Glycogen

Lysosomal Degradation of Glycogen

~1-3% of Glycogen is continuously degraded by lysosomal enzyme α 1-4 Glucosidase Deficiency of this ensyme causes glycogen storage accumulation in vacuoles, resulting in GSD Type II (Glycogen Storage Disease Type II; Pompe disease)