glycogen Metabolims and Gluconeogenesis

what is glycogen

-storage form of glucose

-mobilization of liver glycogen stores provides a constant supply of glucose

-body only stores half-day’s supply of glycogen

significance of branched structure of glycogen

leads to rapid glucose mobilization from nonreducing ends 

efficient compact storage and multiple ends for enzyme action

glycogen function in the skeletal muscle

-glycogen in muscle serves the muscles (lacks glucose-6-phosphatase)

-glycogen breaks down to glucose 1-phosphate, then to glucose-6-phosphate, then used in glycolysis to generate ATP, lactate, or CO2

glycogen function in the liver

-buffer blood glucose concentration

-glucose-6-phosphatase exists to release glucose into blood after glycogen breakdown (converts G6P to glucose)

-serves needs of whole body 

glycogen synthesis

1. formation of G6P from glucose and conversion to G1P

2. synthesis of UDP-glucose from G1P

3. glycogen synthesis from UDP-G

glycogen degradation

1. degradation of glycogen to G1P and 10% glucose

2. conversion of G1P to G6P (and to glucose in liver)

why is UDP-G needed for conversion of G1P to glycogen instead of direct conversion 

direct conversion is unfavorable because not energetically strong enough as G1P is a low energy phosphate donor. UDP-G has an excellent leaving group making its use more favorable 

glycogen synthesis: formation of branched polymer

-polymer attached to glycogenin at reducing end

-glycogen synthases uses UDP-G to extend polymer

-branching enzyme transfers seven-residue segment, breaking linkage and making another linkage

glycogen degradation based on formation of branched polymer

-not reverse of synthesis because not favorable in opposite direction

-glucose molecules removed from non-reducing ends

-branched structure leads to rapid glucose mobilization

-three enzymes required for glycogen breakdown (glycogen phosphorylase, deb ranching enzyme, phosphoglucomutase- G1P to G6P)

what does glycogen storage diseases of liver lead to

hypoglycemia- glycogen cannot be properly broken down into glucose so blood glucose drops

swelling of liver- glycogen cannot be properly broken down so it accumulates in liver

what does glycogen storage diseases of the muscle lead to 

muscle weakness and cramps- during exercise muscles needs quick ATP for contraction and rely on glycogen; without enough ATP muscles fatigue rapidly and cramps develop due to impaired contraction

control of glycogen metabolism

-flux control through regulation of glycogen phosphorylase (activated by AMP and inhibited by G6P) and glycogen synthase (activated by G6P)

-covalent modification (phosphorylation states of glycogen phosphorylase and glycogen synthase provide control for synthesis and breakdown); regulated by hormones insulin, glucagon, and epinephrine

action of kinases and phosphatases that help regulate glycogen metabolism

kinases- when phosphorylated, glycogen phosphylase is active and glycogen synthase is inactive (glycogen breakdown favored)

phosphatases- when dephosphorylated glycogen synthase is active and glycogen phosphorylase is inactive (glycogen synthesis favored)

effect of insulin on glycogen metabolism 

-induces glycogen synthesis

-high insulin in blood signals fed state (abundance of fuel molecules)

-low insulin signals fasted state (increased rate of glucose transport into target cells)

effect of glucagon and epinephrine (fight or flight hormone) on glycogen metabolism 

-trigger glycogen breakdown

-activates protein kinase meaning glycogen degradation is stimulated (breakdown favored when phosphorylated)

different pathways for activation of glycogen phosphorylase in skeletal muscle

1. allosteric activation by AMP (equal to low ATP)

2. activation through an increase in Ca2+(nerve impulse)

3. hormonal activation by epinephrine (glucagon not present in skeletal muscle)

what is gluconeogenesis

process for synthesizing glucose when dietary sources of glucose and glycogen stores are not available (occurs in liver and kidney)

what can be and cannot be converted to glucose in gluconeogenesis

-lactate, pyruvate, glycerol, TCA Cycle intermediated and carbon skeletons of most amino acids can be converted

-fatty acids cannot be converted as animals cannot convert Acetyl-CoA to oxaloacetate

fed, fasting, and starved states 

fed state- blood glucose is high and insulin dominates, gluconeogenesis is minimal because glucose from diet is sufficient and liver maintains stores of glucose as glycogen 

fasting state- occurs several hours after a meal when blood glucose begins to drop, glucagon rises, gluconeogenesis is active using glycerol, amino acids, lactate to generate glucose

starved states-  2 to 3 days of fasting or longer, gluconeogenesis is maximally active using amino acids, glycerol, lactate to make glucose, glycogen stores depleted 

interconversion of pyruvate to PEP in glycolysis and gluconeogenesis

reverse of highly exergonic rxn meaning highly irreversible requires 2 ATP (1 each for pyruvate)

intermediate îs oxaloacetate (uses 1 ATP to go from pyruvate to oxaloacetate)

uses GTP to go from oxaloacetate to PEP

summary of proteins/enzymes/enzyme complexes to know

• Glucose-6-phosphatase – Converts G6P to free glucose in liver/kidney; final step of glycogenolysis and gluconeogenesis.

• Branching enzyme (amylo-α(1,4)→α(1,6) transglucosidase) – Creates α(1→6) branches in glycogen for solubility and rapid synthesis/breakdown.

• Glycogen synthase – Adds glucose units from UDP-glucose to glycogen α(1→4) chains; rate-limiting enzyme of glycogenesis.

• Debranching enzyme – Removes α(1→6) branches during glycogenolysis, allowing glycogen phosphorylase to continue.

• Glycogen phosphorylase – Cleaves α(1→4) bonds at glycogen ends to release G1P during glycogen breakdown.

summary of metabolites/molecules to know

• Glucose – Primary blood sugar and universal energy source.

• Glucose-6-phosphate (G6P) – Key metabolic branchpoint in glycolysis, glycogenesis, and PPP.

• Oxaloacetate (OAA) – TCA cycle intermediate and gluconeogenic precursor.

• UDP-glucose – Activated glucose donor for glycogen synthesis.

• Glycogen – Branched glucose polymer for rapid energy storage.

• Epinephrine – Hormone that stimulates glycogen breakdown and raises blood glucose.

• Glucagon – Hormone that promotes glycogenolysis and gluconeogenesis in the liver.

• Insulin – Hormone that promotes glucose uptake, glycogenesis, and glycolysis.

• Pyruvate carboxylase – Mitochondrial enzyme that converts pyruvate to oxaloacetate in gluconeogenesis.