Glycogen Metabolism and Gluconeogenesis Flashcards

Flashcards reviewing key terms and concepts from a lecture on glycogen metabolism, gluconeogenesis, and related pathways.

Glycogen

Cells readily available energy store

Glycogenin

Glycogen particle core

Glycogen breakdown begins with

Splitting of 𝛂1-4 links and then 𝛂1-6 branch points

Glycogen is abundant in

Liver & muscle

Liver's role in glycogen storage

Glucose buffer for feeding-fasting cycles (energy to entire body)

Muscle's role in glycogen storage

Rapid contraction stimulates immediate breakdown and use of glucosyl units (energy to muscle)

UDP-Glucose

Formed from direct nucleophilic substitution

Low PPi

Keeps UTP glucose synthetase metabolically irreversible

Glycogen synthase

Rate-limiting step in glycogen synthesis

Glycogen synthase

Can be inhibited by gluconolactone

Branching step

Occurs once 10 glucosyl units are added

Glycogen branching enzyme

𝛂1-6 bond (branch point)

Glycogenin

Enzyme & scaffold required for de novo synthesis

Glycogenin structure

A dimer with 2 active sites

UDP-glucose

Donates to glucose residue to tyrosine hydrolysis

Most glycogen synthesis requires

Adding glycogen not de novo

Glycogenolysis

Accomplishes almost all glycogen breakdown

1st step of glycogenolysis

Activation of glycogen phosphorylase by phosphorylation

Glycogen phosphorylase

Breaks down glycogen to glucose-1-phosphate

Debranching enzyme (glucosidase)

Removes branch points and releases free glucose

Phosphoglucomutase

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

Glucose-6-phosphatase

Converts G6P to glucose, which can be released into the blood

Pyridoxal phosphate

Bound cofactor that the glycogen phosphorylase uses

Gluconolactone

Also an inhibitor of glycogen phosphorylase

In muscle

No glucose leaves the cell since there's no glucose phosphatase activity

In the liver

Glucose formation is the fate of glycogen breakdown

Most well established genetic defects due to deranged glycogen metabolism

Involve enzymes of glycogen synthesis/degradation

Increase in cytosolic Ca2+

Muscle contraction & glycogenolysis = glycogen breakdown activated = ATP

Synthesis of glycogen

Under the control of insulin

Glucagon

Hormone that activates liver glycogenolysis

Liver

Can release glucose from glycogen when cytosolic Ca2+ is high from epinephrine release

𝛂-cells of the pancreas

Release glucagon when blood glucose drops

Glucagon

Targets the glucagon receptor of the liver by binding to the surface but never entering the cell

Cytosolic portion of receptor

Binds G Protein (GDP→GTP)

G protein

Leaves the receptor and slides along the membrane when bound to GTP

G protein

Dissociates and binds to a different membrane bound protein adenylate cyclase

Only the GTP bound form of the G protein

Can bind and activate cAMP

G protein

Continues to activate adenylate cyclase until turned off

Ras oncogene

Defect in GTPase of G protein

cAMP

Concentration in the cytosol is increased and binds to protein kinase A

Active PKA

Catalyzes phosphorylation of 2 proteins in glycogen metabolism

Glycogen synthase - phosphorylated

Inactive form reducing rate of glycogen formation

Glycogen phosphorylase kinase - phosphorylated

Active form which increases glycogen breakdown

Down regulation

Epinephrine binding to the receptor

Insulin

Leads to activation of glycogen synthase

AMPK

Found in almost all cells & elevated under deprivation

AMPK

Has to be phosphorylated to be active

Active AMPK in muscle and liver

Inactivates GS and inhibit glycogen synthesis in the muscle and liver

Gluconeogenesis

Utilizes non carbohydrate precursors (amino acids, lactate, triglycerides) to form glucose

Gluconeogenesis

Occurs exclusively in hepatocytes

Gluconeogenesis function

Maintains blood glucose

Standard free energy change of gluconeogenesis

Extremely unfavorable

pyruvate → PEP (phosphoenol pyruvate)

Rate limiting step in gluconeogenesis

Metabolically irreversible enzymes in gluconeogenesis

Pyruvate carboxylase (mitochondrial matrix) & Phosphoenolpyruvate carboxykinase (PEPCK)

Pyruvate carboxylase

Requires biotin (bound cofactor)

Pyruvate carboxylase reaction

Pyruvate + CO2 + ATP → OAA + ADP + Pi

Pyruvate carboxylase

Forms OAA in the mitochondria

Phosphoenolpyruvate carboxykinase (PEPCK) reaction

OAA + GTP → PEP + GDP + CO2

PEPCK

Catalyzes the conversion of OAA to PEP in the cytosol

Glucose 6-phosphatase

Regulated mainly through genetic means

Skeletal muscle

Major glucose consumer in resting state

Glucose utilization during exercise

Increased 100 fold during exercise

Blood

Shunted away from the liver during exercise

Pentose phosphate shunt

Occurs in all cells in the body

Pentose phosphate shunt

Reverse of calvin cycle

Pentose phosphate shunt

Partially oxidized G6P and generates NADPH

Pentose phosphate shunt generates

Sugar phosphates like ribose phosphates which are used in the synthesis of nucleotides

End products of pentose phosphate pathway

Intermediates in glycolysis

All rxns of the oxidative stage of PPP

Metabolically irreversible (G6P + 2NADP+ → Ribulose 5P + CO2+ 2NADPH)

All enzymes in the nonoxidative stage of PPP

Catalyze near equilibrium rxns

Ru5P undergoes 2 rxns

Ru5P → X5P (epimerase) and Ru5P → R5P (isomerase)

R5P fate

R5P → GAP/F6P : intermediates in glycolysis

Transketolase

Cleavage between carbonyl & 𝛂C

Transaldolase

Cleavage between carbonyl & βC

If demand for ribose C increases

More is drawn from the pathway

If NADPH is needed

More C can be returned to glycolytic intermediates and less R5P is removed

Galactose

Metabolized by liver with UDP-glucose

Glycogen Synthase

Adds glucosyl residues to the nonreducing ends of glycogen

Debranching Enzyme

Hydrolyzes alpha-1,6-glycosidic bonds

Fructose-2,6-Bisphosphate

Important allosteric regulator of phosphofructokinase-1

Epinephrine

Stimulates glycogen breakdown in muscle and liver

AMP-activated Protein Kinase (AMPK)

Activated by low energy charge (high AMP/ATP ratio)