Glycogen and the Pentose Phosphate Pathway Flashcards
Glycogen
a highly branched polymer of glucose monomers
found primarily in liver and muscle
can be depleted in 12-24 hours (fasting)
Key regulated enzyme in glycogen synthesis
- glycogen synthase
- catalyzes transfer of glucose from UDP-glucose to growing chain (G6P–>G1P–>UDP glucose)
- forms alpha 1,4 glycosidic linkage (adds to C4 terminus of glycogen)
- glycogen synthase can only add glucose if polysacc chain has been initiated and already contains more than 4 glucose residues
- Glycogenin forms initiating site for glycogen synthesis.
Branching enzyme for glycogen synthesis
- branching enzyme: transfers 6-7 glucose residues to form alpha 1,6 linkages that produce a branch point (at least 4 units away from existing branch point)
- branching provides terminal residues: glycogen breakdown via glycogen phosphorylase
- branching increases rate of glycogen synthesis and degradation
steps of glycogen degradation
- release of G1P from glycogen
- remodeling of the remaining glycogen to permit further degradation
- conversion of G1P to G6P
enzymes:
glycogen phosphorylase
debranching enzyme
phosphoglucomutase
Glycogen phosphorylase
- cleavage of glycogen to G1P
- glycogen released can be converted to G6P by phosphoglucomutase (interconverts between two)
- glycogen phosphorylase STOPS when 4 residues away from alpha 1,6 glycosidic bond branch point.
debranching enzyme
shifts block of 3 glycosyl residues from one outer branch to the other and glycogen phosphorylase continues. This exposes a single glucose residue joined by alpha1,6 glycosidic linkage.
-Glucosidase hydrolyzes the last alpha 1,6 glycosidic bond to yield free glucose molecule.
G6P
in muscle: can enter glycolysis
in liver: can be converted to free glucose and exported to maintain blood glucose levels during fasting state (glucose-6-phosphatase)
Glucagon results in ___
Insulin results in ___
Glucagon (exercise/fasting) results in phosphorylation
Insulin (fed state) results in dephosphorylation
Glycogen synthase activation in liver/ muscle
G6P (+)
Glycogen phosphorylase inhibition/activation in liver/muscle
Liver
G6P (-)
ATP (-)
Glucose (-)
Muscle inhibition: G6P ATP activation: AMP (allosteric/direct) Ca
Activation of glycogen degradation by cAMP producing pathways
-glucagon or epi (counter reg hormones) binds to recep to cell surface–> signals need for glycogen degradation
-2 enzymes are affected: phosphorylase kinase and glycogen phosphorylase
-Binding of epi/gluc activates PKA, which phosphorylates phosphorylase kinase.
-Phosphorylase kinase b (inactive) is converted to phosphorylase kinase a (active) by phosphorylation thru PKA. (Insulin can initiate a cascade that inactivates phosphorylase kinase a using protein phosphatase 1)
-Glycogen phosphorylase also exists in two forms:
dephosphorylated inactive b form
phosphorylated active a form
-Active phosphorylase kinase phosphorylates glycogen phosphorylase b to its active a form, which begins glucose breakdown
-Phosphoprotein phosphatase 1 (PP1) converts glycogen phosphorylase a to b by dephosphorylation
-Phosphorylase kinase b is activated by phosphorylation and phosphorylates glycogen phosphorylase.
Inhibition of glycogen synthesis by cAMP-directed pathway
- Glycogen synthase a and b
- a is the active form, but is DE-phosphorylated
- b is inactive and phosphorylated
- Glucose 6 phosphate binds to an allosteric site on glycogen synthase b: making it a better substrate for dephosphorylation by PP1
- Epi and glucagon lead to activation of cAMP protein kinase (PKA)
- PKA phosphorylates and inactivates glycogen synthase
- PP1 can remove phos groups from: phosphorylase kinase, glycogen phosphorylase, and glycogen synthase
- Insulin stimulates glycogen synthesis by activating PP1 and by inactivating GSK3
What can PP1 dephosphorylate?
phophorylase kinase
glycogen phosphorylase
glycogen synthase
Regulation of glycogen phosphorylase in liver
- low blood glucose, glucagon activates glycogen phosphorylase kinase, which converts b to a form of glycogen phosphorylase–> glucose into blood
- glucose normal: glucose enters hepatocytes and binds to allosteric site on glycogen phosphorylase a–> conformational change–> phosphatase removes phos, converts it to inactivate glycogen phosphorylase b, turns off glycogenolysis and glucose release
What inhibits glycogen phosphorylase?
ATP
G6P
Glucose (liver)
AMP (muscle)
What does the Pentose phosphate pathway produce?
- NADPH (for synth of fatty acids and steroids)
- ribose-5-phosphate (for synthesis of nucleotides– purines and pyrimidies (like ATP, GTP, UTP)
- glycolytic intermediates
NADPH is part of oxidative phase
ribose 5 phosphate and glycolytic int part of non-oxidative phase
Enzymes of pathway located in cytosol.
Where is the PPP prominent?
mammary gland adrenal cortex liver adipose tissues (where fatty acid and steroid synthesis are common)
First rxn in PPP
- first rxn is catalyzed by glucose-6-phosphate dehydrogenase (G6PD) (key committed and rate related step)
- generates first NADPH
- a subsequent step of dehydrogenation and decarboxylation produce another NADPH and 5 C sugar ribulose-5-phosphate
Oxidative vs non-oxidative phase of PPP
oxidative: generates NADPH
Non-oxidative: interconverts sugars back to glucose-6-phosphate if more NADPH or pentose phosphates are needed or to glycolytic intermediates if more energy is needed.
-rearrangements/transfers convert ribulose-5-phosphate to ribose-5-phosphate and to glycolytic intermediates. Accomplished by transfer of 2C and 3C units. (3 5C sugars are converted to 2 6C sugars and 1 3C sugar)
G6PD deficiency
- NADPH provides the reducing equivalent for redox rxns, esp those involving glutathione (GSH).
- NADPH maintains glutathion in a reduced state
- G6PD deficiency? unable to regenerate GSH to guard agains ROS, and sulfhydryl groups in hemoglobin become oxidized–> cross links and aggregates in RBCs called “Heinz bodies”
- rigid RBC membranes leading to destruction and hemolytic anemia
