Chpt 21: Glycogen Metabolism Flashcards
Glycogen Anabolism
stores glucose
Glycogen Catabolism
Breakdown/releases glucose
Sources of glucose
- Diet
- Degradation of glycogen
- Gluconeogenesis
Glycogen
1) is a branched-chain homopolysaccharide made from alpha-D-glucose
- alpha 1,4 glycosidic bonds
- alpha 1,6 glycosidic brances
* branching increases solubility of glycogen
2) ready supply of glucose
- liver glycogen provides glucose to blood
- Skeletal muscle glycogen provides energy for muscle contraction
3) Glycogen storage
- increases during well-fed state
- depleted during fasting state
4) stored in cytoplasm
Breakdown of Glycogen
1) Glycogen (x) + orthophosphate (Pi) -> Glycogen (x-1) + glucose 1-Phosphate catalyzed by glycogen phosphorylase and continues until its 4 glucose residues from alpha 1,6-branch
2) Glycogen (4 residues from branch)-> Glycogen (x+3) catalyzed by Oligo-alpha (1-4)-alpha(1-6)-glucan transferase
- transfers 3 glucose residues from branch to main chain
3) Glycogen (x-1) with final branch residue-> Glycogen (x-1) + glucose (free) catalyzed by Amylo alpha-(1-6) glucosidase
- Hydrolysis reaction OTHER REACTIONS ARE PHOSPHOROLYSIS REACTIONS
Debranching enzymes
Bifunctional Enzyme
1) Oligo-alpha(1-4)-a(1-6)-glucan transferase
- transfers 3-4 residues at branch to another chain thus lengthening the “other” chain by 3-4 residues
2) Amylo-alpha(1-6) glucosidase
- releases free glucose from residue at Alpha 1,6 branch via HYDROLYSIS (ADDITION OF WATER)
Liver vs Muscle Glycogen Metabolism
Liver cells (hepatocytes) contains Glucose 6-phosphatase which provides free glucose for cell (distribution via blood)
Muscles Cells lack glucose 6-Phosphatase so the Glucose 6-Phosphate enters glycolysis to provide ATP for muscle contraction
Liver specific glycogen catabolism
1) Glycogen(x) + Pi -> Glycogen (x-1) + Glucose 1-Phosphate via glycogen phosphorylase
2) Glucose 1-Phosphate -> Glucose 6-Phosphate (cytosol) catalyzed via phosphoglucomutase (cytosol)
3) Glucose 6-Phosphate (cytosol)-> Glucose 6-Phosphate (lumen of ER) via Glucose 6-Phosphate translocase
4) Glucose 6-Phosphate (lumen of ER)-> Glucose (blood) via Glucose 6-Phosphatase (ER)
Glycogen Phosphorylase
-structure
Homodimer
1) N-terminal domain:
- Glycogen binding site
- Catalytic site between the two domain
2) C-terminal domain
PLP-pyridoxal Phosphate- Prosthetic group
Glycogen Phosphorylase
-function
Catalyzes the sequential removal of Glucose 1-Phosphate from nonreducing end of glycogen via Phosphorylysis until it reaches 4 residues from branch then requires debranching enzymes
-Not hydrolysis-water excluded from active site
PLP
Pyridoxal Phosphate
Prosthetic Group of Glycogen Phosphorylase
-attached to lysine of enzyme through Schiff’s base
Function:
- Group transfer to or from amino acids
- Proton donor/acceptor
Vit-Pyridoxine (B6)
Deficiency:
-Depression, Confusion, Convulsion
Glycogen Phosphorylase Regulation
Regulation:
1) Allosteric- Tissue Specific
- Liver
- Muscle
* different in liver and muscle due to different effectors
2) Reversible Phosphorylation-Hydroxyl of Ser
- a form=phosphorylated
- b form=dephosphorylated
3) Calcium
- only in muscle
- release of calcium triggers contraction from sarcoplasmic reticulum
Alternate between Two Forms:
1) Phosphorylase A:
- active form
- may exist in either T or R state
2) Phosphorylase B:
- inactive form
- May exist in either T or R state
Liver and muscle cells differ in response to Inhibitors:
-Isozymes~90% identical
T and R state of Phosphorylase
Each form (a and b) exists in equilibrium of one of two states:
1) Tight (T) state
- inactive form
- favored by Phosphorylase b (dephosphorylated form)
2) Relaxed (R) state
- active form
- favored by Phosphorylase a (Phosphorylated form)
Phosphorylation of Ser converts B to A
Allosteric Regulation of Muscle Glycogen Phosphorylase
Muscle Glycogen Phosphorylase releases Glucose 6-Phosphate for use by the muscle cell for production of ATP to power contraction
- Resting muscles contain mostly Phosphorylase B
- exercise stimulates conversion of phosphorylase B->A by phosphorylating OH of serine
Muscle Phosphorylase A:
- Hormonal Signals stimulates phosphorylation of B-> A by a phosphorylase kinase
- always active:
1) release glucose to synthesize ATP for muscle contraction
2) independent of [AMP], [ATP], [G6P]
Muscle Phosphorylase B: 1)Stimulated by: High [AMP] increases activity -binds to nucleotide binding site -release glucose to produce ATP Indirectly High [Ca2+] increases activity 2)Inhibited By High Energy Charge: High [ATP] decreases activity -competes with AMP for nucleotide binding site High [G6P] decreases activity
Allosteric Regulation Liver Glycogen Phosphorylase
Liver Glycogen Phosphorylase functions to release glucose from the liver for transport to other tissue via blood
High glucose concentration decreases activity:
-If blood glucose is high then glycogen catabolism is not needed to produce free glucose
Hormonal Regulation:
-Liver and Muscles
Glucagon (to a lesser extent epinephrine (adrenaline))
-Liver-stimulates glycogen catabolism-release of glucose in blood
Epinephrine (adrenaline)
-Muscle-stimulates glycogen catabolism-release of glucose for glycolysis
Epinephrine (Adrenaline)
1) Catecholamine derived of tyrosine
2) Synthesized in adrenal medulla
- located in adrenal glands on top of kidney
3) Released in response to low blood glucose concentration
4) Stimulates catabolism of glycogen in muscles (and lesser extent in liver)
- In muscles bind to B-adrenergic receptor
- in liver binds to:
a) B-adrenergic receptor
b) A-adrenergic receptor-Phosphoinositide cascade which stimulates Ca2+ release
Glucagon
Peptide Hormone
- Secreted by alpha cells of pancreas
- Released in response to low blood glucose concentration (starved state)
- Stimulates catabolism of glycogen in liver by binding to glucagon receptor
Glycogen Phosphorylase Signal Transduction Pathway
1) Epinephrine (Muscle) or Glucagon (Liver) binds to 7TM receptor(B-adrenergic receptor) which stimulates activation of 100 G proteins
2) Active G protein binds to and activates Adenylate Cyclase
3) Adenylate Cyclase synthesizes cAMP using ATP as substrate (alot of ATP used)
4) cAMP activates Protein Kinase A by binding to the Regulatory Subunit
5) Protein Kinase A phosphorylates Phosphorylase Kinase (active)
6) Phosphorylase Kinase phosphorylates OH of Ser on glycogen Phosphorylase which converted B-> A (TURNED ON)
7TM Receptor
-function/structure
Seven Transmembrane-helix receptor 50% of therapeutic drugs target this class of receptors -B adrengernic receptors are members of this class
7 Membrane spanning alpha helixes
Binding of hormone stimulates activated of G proteins
-1 receptor activates 100s of G proteins
G Protein
-function/structure
Heterotrimeric protein binds guanyl nucleotides
Heterotrimer:
-Ga(alpha subunit)-nucleotide binding subunit, in active/stimulated form it binds to adenylate cyclase
a) Inactive form bound to GDP
b) Active form bound to GTP
c) Member of P-loop ATPase family
Gby (beta/gamma subunit)-exchanges GDP for GTP on alpha subunit
Adenylate Cyclase
-function
Amplifies signal of hormone by synthesizing cAMP
Protein Kinase A
- structure
- function
Heterotetramer of two subunits-R2C2
1) catalytic (C) subunit
- Phosphorylates target protein when freed from R subunit
- Protein Kinase activity
2) Regulatory (R) Subunit
- each binding site contains 2 binding sites for cAMP
Stimulates glycogen breakdown
Inhibits glycogen synthesis by phosphorylating glycogen synthase
Phosphorylase Kinase
Kinase that activates glycogen phosphorylase by phosphorylation of serine which converts it from b form to A form
Has several forms: subunit composition ABYDx4
- Y subunit-catalytic subunit
- ABD regulatory subunit
1) D subunit (calmodulin)-binds Ca2+ - serves as Ca2+ sensor
- activates many pathways
- contains 4 calcium binding sites
2) B subunit is target for phosphorylation
Duel Control:
1) Phosphorylation ser activated by protein kinase A
2) Calcium-which is released from sarcoplasmic reticulum due to nerve impulse to stimulate muscle contraction
Lysosomal Degradation of Glycogen
alpha (1-4) glucosidase (aka acid maltase)
-degrades glycogen from vacuoles in cytoplasm
Glycogen Synthesis Overview reaction
1) alpha-D-glucose-> Glucose 6-Phosphate catalyzed by Hexokinase at the expense of ATP-> ADP
2) Glucose 6-Phosphate-> Glucose 1-Phosphate catalyzed by phosphoglucomutase
3) Glucose 1-Phosphate-> UDP Glucose catalyzed by UDP Glucose pyrophosphorylase at expense of UTP
4) UDP-Glucose-> Glycogen catalyzed by Glycogen Synthase
Hexokinase
Glycolytic Enzyme
Converts:
Alpha-D-Glucose-> Glucose 6-Phosphate at expense of ATP
Phosphoglucomutase
Interconverts Glucose 1-Phosphate and Glucose 6-Phosphate
UDP-glucose pyrophosphorylase
Converts
Glucose 1-Phosphate + Uridine Triphosphate (UTP)-> UDP-Glucose + Pyrophosphate (PPi)
Pyrophosphate is hydrolyzed to 2Pi (orthophosphates) to provide energy
Inorganic Pyrophosphatase (Pi)
Hydrolyzes PPi-> Pi + Pi
-exergonic-> drives glycogen synthesis
Glycogen Synthase
UDP-Glucose + existing Glycogen molecule-> UDP + Glycogen (n+1)
adds glucose to glycogen
- requires existing polymer of glycogen with at least 4 glucose residues
- glycogenin
Nucleotide diphosphate Kinase
Regenerates UTP
UDP + ATP-> UTP + ADP
Glycogenin
Serves as a primer for glycogen synthesis
- contains tyrosine residue-OH
- location where glycogen molecules have glucose released/attached
Branching Enzyme
synthesizes alpha 1-6 branches every 8-10 glucose residues during glycogen anabolism
Insulin
Peptide Hormone
- secreted by islets of Langerhans in pancreas
- released in response to high blood glucose concentration (Well fed state)
- Stimulates anabolism of glycogen in liver (NOT MUSCLE) by binding to insulin receptor
Protein Phosphatase 1
Dephosphorylates Ser and Thr
- Dephosphorylates glycogen synthase b (inactive form) converting it into glycogen synthase a (active form) which stimulates glycogen synthesis
- Dephosphorylates phosphorylase kinase inhibiting glycogen breakdown
