Glycogen Metabolism Flashcards
Glycogen is synthesized in ______ steps from G6P. G6P is produced from glycogen in _____ steps
Glycogen is synthesized in 4 steps from G6P. G6P is produced from glycogen in 3 steps
Glucose monomers are released from the nonreducing ends of glycogen by ________.
Glucose monomers are released from the nonreducing ends of glycogen by glycogen phosphorylase, and debranching enzyme.
Mechanism for glycogen phosphorylase:
Phosphorolysis (rather than hydrolysis) reduces the need to expend ATP to phosphorylate the glucose monomer released from glycogen but….
…but releases G1P and not G6P
Draw the mechanism for Phosphoglucomutase
In liver, G6P is hydrolyzed to _______
In liver, G6P is hydrolyzed to glucose forexport to the cirulatory system
Mechanism for Glycogen synthase
Describe: Control of flux through pathways
1) Enzymes which catalyze reactions with ∆G <<0 are often sites of regulation, responsive to local (e.g., allosteric) and global (e.g., hormonal) regulatory signals.
2) Coordinated control of multiple regulatory enzymes, where different tissues may respond differently to the same global signal. May involve a complex interplay of covalent modification and/or binding to regulatory subunits.
3) Sequestration/de novo synthesis of key enzymes in response to global signals.
Example of Control of flux through pathways: Allosterics
- (glycogen) Phosphorylase
- PFK-1 (atp and FBP)
Control of flux through pathways: Tissues
Control of flux through pathways: Covalent modification
Control of flux through pathways: Global Signals
Regulation in response to “energy charge” is often mediated by _________.
Regulation in response to “energy charge” is often mediated by pathway enzymes that are, in turn, activated/inhibited by changing concentrations of adenylates
Regulation inresponse to“energy charge”can also bemediated by non-pathway enzymesthat are _________.
Regulation inresponse to“energy charge”can also be mediated by non-pathway enzymes that are “global regulators” which are responsive to changing concentrations of adenylates
Control of flux through pathways: Sequestration/de novo synthesis of key enzymes inresponse to global signals.
- Major control mechanismsaffecting glycolysis andgluconeogenesis
- Conditions that promote glycolysis inhibit gluconeogenesis, and vice versa.
Example: Different issues may have different isozymes, which respond differently to regulatory signals
HK-I (muscle) vs HK-IV (liver)
Example: Opposing enzyme activities respond to signals in a reciprocal fashion
PFK-1 vs. FBPase-1: Opposing enzyme activities respond to signals in a reciprocal fashion
How is T and R state affected by PFK-1 vs. FBPase-1?
Example: Opposing enzyme activities encoded on a singlepolypeptide, with tissue-specific responses to external stimuli
PFK-2 vs FBPase-2:
- Fructose-2,6-bisphosphate is the most important regulator of glycolysis and gluconeogenesis.
- It is synthesized and degraded by opposing activities, encoded in distinct domains of the same protein.
- In liver tissue these activities are responsive to phosphorylation:
What enzyme is the most important regulator of glycolysis and gluconeogenesis?
Fructose-2,6-bisphosphate is the most important regulator of glycolysis and gluconeogenesis.
Example:
Opposing enzymeactivities respond tosignals in a reciprocalfashion
F26BP is the most potent allostericeffector of PFK-1
What does Insulin do?
general signal for dephosphorylation of proteins
What does Glucagon/epinephrine do?
general signal for increased protein phosphorylation
The synthesis of F-2,6-BP is ________ control in _____ cells
The synthesis of F-2,6-BP is underhormonal control in liver cells
Describe how the synthesis of F-2,6-BP is underhormonal control in liver cells
- PFK-2/FBPase-2 is controlled by reversible phosphorylation of Ser32 in each subunit of the homodimeric protein.
- In the unphosphorylated form, the kinase domain (K) is active, and F-2,6-BP is synthesized.
- In the phosphorylated form, the phosphatase domain (B) is active, and F-2,6B-P is degraded.
- Glucagon stimulates phosphorylation by activating cAMP-dependent protein kinase (PKA). Insulin and glucose stimulate dephosphorylation by activating a protein phosphatase.
Liver hexokinase is also regulated by ________
Liver hexokinase is also regulated by protein–protein interactions.
- Liver HKIV is interacts with the glucokinase regulatory protein (GKRP) in the nucleus anddephosphorylated PFK- 2/FBPase-2 in the cytoplasm.
- Insulin binding to its plasma membrane receptor stimulates dephosphorylation of PFK-2/FBPase-2.
Example: Different Tissues may have different isozymes, which respond differently to regulatory signals.
Describe Feedback control
Feedback control can upregulate or downregulate the activities of key enzymes.
Epinephrine and “fight or flight”
Result: net degradation of glycogen to release glucose; but,what happens to the glucose differs between liver and muscle
In response to stress (i.e., release of epinephrine) the liver ________ glucose.
In response to stress (i.e., release of epinephrine) the liver EXPORTS glucose
In response to stress (i.e., release of epinephrine) muscle _________ glucose (to make ATP)
In response to stress (i.e., release of epinephrine) muscle CONSUMES glucose (to make ATP)
Phosphorylase kinase A is maximally activated in the __________.
Phosphorylase kinase A is maximally activated in the presence of Ca2+ (which is released in sarcomere when muscles contract)
Different responses in muscle and liver are largely due to ____________
Different responses in muscle and liver are largely due to different responses of PFK-2/FBPase-2 to external stimuli in these tissues
Regulation of glycogen metabolism: Draw a graph of phosphorylase A and glycogen synthase with x=time and y=ezyme activity
Glucose binding results in a _________ that makes phospho-Ser14 accessible to the PP1 phosphatase.
Glucose binding results in a conformational change that makes phospho-Ser14 accessible to the PP1 phosphatase.
Draw the T and R forms of Phosphorylase A and B
Why do these effects make biochemical sense?
Why do these effects make biochemical sense?
