Metabolism of glycogen

Regulation of glycogen metabolism

• Regulating site for glycogen synthesis

Glycogen synthase

• Regulating site for glycogen catabolism

Glycogen phosphorylase

Glycogen Phosphorylase AMP activates Phosphorylase

ATP & glucose-6-phosphate inhibit Phosphorylase

Thus glycogen breakdown is inhibited when ATP and glucose-6-phosphate are plentiful.

Glycogen Synthase Activated by glucose-6-P (opposite of effect on Phosphorylase).

Thus Glycogen Synthase is active when high blood glucose leads to elevated intracellular glucose-6-P.

Regulation by hormones

Glucagon and epinephrine:

• Inhibit glycogen synthase

• Activate glycogen phosphorylase

• Increase glycogen catabolism and increase blood glucose

Insulin:

• Inhibit glycogen phosphorylase

• Activate glycogen synthase

• Increase glycogen synthesis and decrease blood glucose

Regulation of Glycogen Phosphorylase by Hormones

Regulation of Glycogen Synthase by Hormones

Glycogen Function

• In liver – The synthesis and breakdown of glycogen is regulated to maintain blood glucose levels.

• In muscle - The synthesis and breakdown of glycogen is regulated to meet the energy requirements of the muscle cells.

Gluconeogenesis

• A metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates.

• It is one of the two main mechanisms the body uses to keep blood glucose levels from dropping too low .

• In animals, gluconeogenesis takes place mainly in the liver.

• This process occurs during periods of fasting, starvation, or intense exercise.

Basically, gluconeogenesis pathway is a reverse of glycolysis but has three bypass.

Irreversible glycolytic stepsbypassed

1. Hexokinase

2. Phosphofructokinase-1

3. Pyruvate kinase (PyrK)

by Glucose-6-phosphatase

by Fructose 1,6-bisphosphatase

by Pyruvate Carboxylase and Phosphoenolpyruvate carboxykinase

Glycolysis Gluconeogenesis

Glucose-6-Phosphatase catalyzes: glucose-6-phosphate + H2O glucose + Pi

• This is primarily a function of the liver to buffer blood glucose levels

• Glucose-6-Phosphatase is NOT present in brain and muscle!

Bypass 1:

Fructose-1,6-bisphosphatase catalyzes: fructose-1,6-bisP + H2O fructose-6-P + Pi

Bypass 2:

Bypass 3:

Pyrovate carboxylase and PEP carboxykinase catalyze:

Pyruvate + ATP+ GTP PEP + ADP + GDP + Pi + CO2

Gluconeogenesisas it takes place in the mammalianliver.

PEP carboxykinase locates in bothcytosol and mitochondral. So there are two ways to transfer pyruvate to PEP.

Lactate feed into gluconeogenesis through pyruvate.

Lactate dehydrogenase

Intermediates in citric acid cycle can be used for gluconeogenesis through oxaloacetate

PEP

All amino acids can feed into gluconeogenesis except leucine and lysine.

Pyruvate can go “up” or “down”

depending upon energy needs

Liver is the major source of blood glucose from gluconeogenesis

Is the primary gluconeogenic organ

Produces glucose for export to brain, muscle, RBC’s

Uses many small metabolites and amino acids to feed gluconeogenesis

Liver function is highly sensitive to insulin & glucagon

Cori CF

• Lactate and glucose shuttle between active muscle/RBC and liver

•Liver gluconeogenesis supplies the blood glucose for use by muscle, RBC’s and brain (120 g/day)

• Note: the brain fully oxidizes glucose, so it does not funnel back lactate

• The liver can also use the amino acid Alanine similarly to Lactate

• Following transamination to pyruvate, gluconeogenesis allows the liver to convert it to glucose for secretion into the blood

Regulation of gluconeogenesis

To prevent the waste of a futile cycle, Glycolysis & Gluconeogenesis are reciprocally regulated.

F-1,6-Bisphosphatase is the most important control site in Gluconeogenesis.

Reciprocal regulation by ATP/AMP AMP inhibits Fructose-1,6-bisphosphatase but activates

Phosphofructokinase ATP inhibits Phosphofructokinase but activate Fructose-1,6-

bisphosphatase In high ATP/AMP ratio: stimulate gluconeogenesis In low ATP/AMP ratio: stimulate glycolysis

Reciprocal regulation by fructose-2,6-bisphosphate:

Fructose-2,6-bisphosphate stimulates Glycolysis.

Fructose-2,6-bisphosphate activates Phosphofructokinase-1.

Fructose-2,6-bisphosphate inhibits Fructose-1,6-bisphosphatase.

Reciprocal regulation by hormones Phosphofructokinase-1 (PFK-1)

Induced in feeding by insulin Repressed in starvation by glucagon

Fructose-1,6-bisphosphase Repressed in feeding by insulin Induced in starvation by glucagon

So: Insulin activates glycolysis but inhibits gluconeogenesis; Glucagon activates gluconeogenesis but inhibits glycolysis.

Metabolism of fructose

Fructose is metabolized in the liver

Metabolism of galactose

The first enzyme to act on galactose is galactokinase. This converts galactose into galactose-1-phosphate.

Galactose-1-phosphate uridyl transferase produces UDP-galactose and Glucose-1-Phosphate from galactose-1-phosphate and UDP-glucose.

UDP-Galactose

UDP-galactose-4-epimerase produces UDP-glucose.

Phosphoglucomutase catalyzes the reversible reaction:

glucose-1-phosphate glucose-6-phosphate

The Entry of galactose into glycolysis and glyconeogenesisFructose is metabolized in the liver.

You should know:

1. Chemical steps of gluconeogenesis; associate enzymes

2. Precursors that can enter gluconeogenesis;

3. Relationship of glycolysis to gluconeogenesis; shared enzymes, irreversible steps

4. Liver as the primary gluconeogenesis organ; Cori Cycle, Alanine Cycle.