Lecture 23 Flashcards
State the enzymes that are the rate limiting step of glycogen synthesis and glycogen breakdown
glycogen synthesis: GS (glycogen synthase)
glycogen breakdown: GP (Glycogen phosphorylase)
Glycogen synthase exists in 2 forms, the A form and the B form. Describe which of these is “phosphorylated/dephosphorylated” and which of these is considered “active/inactive”
A is the active form and is NON-phosphorylated
B is the inactive form and is phosphorylated
(phosphate turns it off ; only 2 total forms of GS)
Which protein is responsible for the phosphorylation of Glycogen Synthase? state the 2 substances that control it and the molecule that stabilizes its active form via allosteric regulation.
GSK (glycogen synthase kinase)
GSK is under control of insulin and PKA
GKS is allosterically controlled by gluc-6-phosphate (powerful activator)
Glycogen Phosphorylase exists in 2 forms, the A form and the B form. Compare these 2 forms in terms of the phosphorylated form, the active form and the tensed form. explain where in the body these “forms” of GP (Glycogen phosphorylase) can be found by default.
A form: the phosphorylated form of GP
The active form is the A form
This is the default form in the liver
B form: the non-phosphorylated form of GP
The inactive form is the B form
This is the default form in muscle tissue
Both of these forms exist in equal equilibriums of the relaxed state (exposes active site) and the tensed state (closes off the active site)
(technically there are 4 possible forms of GP)
GP is regulated by allosteric effectors and phosphorylation. What do these 2 regulatory methods respond to?
Allosteric effectors signal the energy state of the cell (lots of Gluc-6-phosphate means there is enough extra to make glycogen)
phosphorylation is responsive to hormones (glucagon and insulin)
The liver (A form) and muscle (B form) forms of GP are products of separate genes, meaning they are _____. Quickly explain what this means
Isozymes
They differ in sensitivities to regulatory molecules
True or False:
AMP serves to allosterically activate the muscle and liver forms of GP. explain.
False
AMP only allosterically activates the muscle form. The liver form is UNAFFECTED by AMP.
What effect does free glucose have on Liver GP? explain the mechanism that causes this.
Liver GP is Inactivated by glucose
glucose allosterically binds to the active site and stabilizes the inactive T state conformation (so thats phosphorylase A in it’s T form)
(this makes sense because when there is excess glucose, glycogen does not need to be converted to glucose)
Under normal physiological conditions, what form is Muscle GP found in? why?
the inactive (default in muscle cells), B form
This is because ATP and gluc-6-phosphate exhibit inhibitory effects on Muscle GP
what effect does AMP have on muscle GP? explain the mechanism that causes this.
AMP activates Muscle GP
AMP allosterically binds to the active site and stabilizes the active R state (so thats phosphorylase B in its R form)
Compare the molecules that allosterically regulate muscle and liver GP, respectively.
Muscle GP is allosterically activated by AMP (bc muscle contraction converts ATP to AMP)
Muscle GP is allosterically inactivated by ATP and gluc-6-phosphate
Liver GP is inactivated by glucose
The phospho form of glycogen synthase is _____ . The phospho form of glycogen phosphatase is ______.
Inactive
Active
Answer glycogenolysis or glycogenesis to the following states.
Fed state:
Fasting state:
During exercise:
Fed state: glycogenesis (make glycogen)
Fasting state: Glycogenolysis (break down glycogen)
During exercise: Glycogenolysis (break down glycogen)
Under fed conditions, describe how insulin affects GS and GP. (include secondary messengers, enzymes, and whether they are phosphorylated or dephosphorylated)
(Insulin reacts with it’s RTK receptors to cause the secondary messenger PKB to affect enzymes)
PKB activates PP1 (via phosphorylation) which activates GS via dephosphorylation
PKB inactivates GSK3
PKB also activates GLUT4 (insulin reg. one) which moves to the membrane to bring in glucose
PKB activates PP1 (via phosphorylation) which inactivates GP and PK (the kinase that phosphorylates GP) via dephosphorylation
Explain type 2 diabetes in terms of the mutations that cause it. also state diabetic blood glucose values
mutations in insulin receptor and/or downstream signalling proteins (such as the ones that move GLUT4 to the membrane) that lead to insulin resistance and hyperglycemia
70-100 = normal blood glucose 100-125 = pre diabetic blood glucose >125 = diabetic blood glucose
What 2 hormones are released when blood sugar levels get low or when muscle activity increases? what type of receptors do these hormones interact with?
Glucagon is released when blood glucose is low
Epinephrine is released when muscle activity increases
Both glucagon and epinephrine hormones are mediated via GPCR’s
what enzyme do glucagon and epinephrine effect and what way do they affect it? explain the effect of these 2 hormones on liver and muscle cells respectively.
epinephrine and glucose activate GP, which stimulates glycogen breakdown
Epinephrine acts on the liver and muscle cells
Glucagon acts on the ONLY the liver
Conversion initiated by ______ stimulates the phosphorylation of a single AA residue to convert from the B to the A form of GP (glycogen phosphorylase).
Which AA residue gets phosphorylated? What protein phosphorylates GP to trigger Glycogenolysis?
Hormones
Serine
PK phosphorylates GP to trigger glycogenolysis
explain the 2 step process that must occur to PK in order to “fully activate” it so that it may phosphorylate GP (activating it from it’s B to A form).
Ca2+ from muscle contraction and nerve impluses partially activates PK
PKA triggered by hormones then phosphorylates the subunits of PK
Explain the steps that occur when Glycogenolysis is being triggered by glucagon and epinephrine hormones
(these hormones interact with GPCRs to make cAMP from ATP)
cAMP stimulates PKA
PKA phosphorylates an inhibitor that inhibits PP1
PKA also inhibits GS via phosphorylation
PKA phosphorylates PK which activates GP via phosphorylation
For the following allosteric Epinephrine regulators, describe their effect.
gluc-6-phosphate:
Free glucose:
Ca2+:
AMP:
gluc-6-phosphate: activates GS and inactivates GP
Free glucose: inhibits GP (IN THE LIVER ONLY not in muscle)
Ca2+: activates PK (GPK, which goes on to activate GP)
AMP: activates GP
Compare the fate of Gluc-1-phosphate in the liver and muscle tissues.
In the liver: glu-1-P is converted to glu-6-P
Then to free glucose by glucose-6-phosphatase enzyme (only present in the liver)
In muscle tissues: Glu-1-P is used to create energy via glycolysis and the TCA cycle
(has no glucose-6-phosphatase enzyme)
Which enzyme is considered to the be the “glucose sensor” in liver cells?
Glycogen phosphorylase (GP)
For the following Glycogen-storage disease, state the Defective Enzyme, The organ(s) affected, and what occurs to the glycogen in the affected organ.
Type I ; Von Gierke
Type I Von Gierke
Defective Enzyme: Gluc-6-phosphatase (or transport system)
Organ(s) affected: Liver and Kidney
Glycogen in organ: Increased amount ; normal structure
