glycogen metabolism II Flashcards
regulation of glycogen metabolism is very important to
maintain blood sugar and provide energy to muscles
rate limiting enzyme of glycogen synthesis
glycogen synthase
rate limiting enzyme of glycogen degradation
glycogen phosphorylase
glycogen synthase and glycogen phosphorylase (rate limiting enzymes of glycogen synthesis and degradation) are regulated by
allosteric regulators and by reversible phosphorylation (under the control of hormones)
glycogen synthase exists in 2 forms
- non-phosphorylated “a” form -active form
2. phosphorylated “b” form - inactive form
glycogen synthase is phosphorylated by ______ and dephosphorylated by ______
glycogen synthase kinase (GSK)
protein phosphatase
glycogen synthase kinase (GSK) is under the influence of
insulin
allosteric regulation - power activator of glycogen synthase
glucose 6-phosphate
glycogen phosphorylase exists in 2 forms
- phosphorylated “a” form - active form (R relaxed state) - in liver
- dephosphorylated “b” form - inactive form (T tense state) - in muscle
glycogen phosphorylase is regulated by
several allosteric effectors (signal energy state of the cell)
reversible phosphorylation (responsive to hormones)
liver and muscle forms of glycogen phosphorylase (GP) are products to 2 separate genes, they are called
isozymes
liver and muscle forms of glycogen phosphorylase (GP) differ in their
sensitivities to regulatory molecules
liver glycogen phosphorylase (GP) is inactivated by
free glucose (indicator of blood sugar levels); unaffected by AMP
muscle glycogen phosphorylase (GP) is allosterically activated by
AMP (measure of low energy status of cell)
allosteric regulation of liver glycogen phosphorylase (GP):
glucose binds to active site and
when glucose levels are high, no need for
stabilizes conformation in the inactive T state
glycogen breakdown (which would make more glucose)
default form of liver glycogen phosphorylase is
“a” form or active form
allosteric regulation of muscle glycogen phosphorylase (GP):
AMP bind to active site and
ATP and glucose-6-phosphate are
under normal physiological conditions, GP is inactive because of
stabilizes conformation of “b” in the active R state
negative allosteric regulators
inhibitory effect of ATP and gluc-6-phosphate
default form of muscle glycogen phosphorylase is
“b” form or inactive form
glycogenesis is favored in fed state:
blood glucose is ______
insulin is ______
cellular ATP is ______
high
high
high (signal of high energy)
when glycogen synthesis is favored:
_______ form of glycogen synthase is dominant
_______ form of glycogen phosphorylase is dominant
dephosphorylated form (active)
dephosphorylated form (inactive)
glycogenolysis is favored in fasting state and during exercise:
blood glucose is ______
glucagon is ______
cellular calcium is ______
AMP is ______
low
high
high (in exercising muscles)
high (from breakdown of ATP)
when glycogen breakdown is favored:
_______ form of glycogen synthase is dominant
_______ form of glycogen phosphorylase is dominant
phosphorylated form (inactive)
phosphorylated form (active)
Regulation of glycogen metabolism by insulin: glycogen synthase activation by insulin:
insulin binds to insulin receptor (receptor tyrosine kinase in muscle and liver) –> through signaling activates _____ –> PkB phosphorylates and activates _____ while phosphorylating and inactivating ______ –> PPI dephosphorylates ______ ______ (which is now activated) to proceed with glycogenesis
protein kinase B (PkB)
protein phosphatase I (PPI)
glycogen synthase kinase 3 (GSK3 typically phosphorylates glycogen synthase inactivating it)
glycogen synthase
additional function of PkB
responsible for insertion of GLUT4 into plasma membrane
regulation of glycogen metabolism: glycogen phosphorylase inactivation
insulin binds to insulin receptor (receptor tyrosine kinase) through signaling activates ______ –> PkB phosphorylates and activates _______ which inactivates ______ ______ and ______ ______ –> making glycogen phosphorylase inactive (preventing glycogenolysis from occuring)
protein kinase B (PkB)
protein phosphatase I (PPI)
glycogen phosphorylase
phosphorylase kinase (PK)
active protein phosphatase I (PP1) dephosphoyrlates ________ and dephosphorylates _______
glycogen synthase (activates)
glycogen phosphorylase (inactivates)
mechanism of regulation by insulin:
net result: glycogen synthesis via
activation of glycogen synthase and inactivation of glycogen phosphorylase
type 2 diabetes:
called:
mutations in:
insulin resistance
insulin receptor and/or downstream signaling proteins
type 2 diabetes:
down-regulation in receptor levels:
triggered by elevated insulin
endocytosis and degradation of the insulin receptor
defective receptors not replaced by translation
normal blood glucose:
prediabetic/at-risk:
diabetes mellitus:
70-100 mg/dL (fasting) ; less than 140 (fed)
100-125 mg/dL (fasting) ; greater than 140 (fed)
greater than 126 mg/dL (fasting) ; greater than 199 (fed)
low blood sugar levels release
glucagon (acts on liver)
muscle activity releases
epinephrine (effects are on muscle)
glucagon and epinephrine are mediated by what type of receptors
GPCRs
epinephrine and glucagon signal
glycogen breakdown
phosphorylase kinase (PK) phosphorylates
glycogen phosphorylase to make it active
phosphorylase kinase (inactive) –> _______ (partly active)
Ca 2+ (exercising muscle)
Ca2+ actually binds to calmodulin
phosphorylase kinase (partly active) –> ________ (fully active)
PKA (which is activated by glucagon and epinephrine)
phosphorylated form (phosphorylase a) (active form)
regulation of glycogenolysis by glucagon and epinephrine: glycogen synthase inactivation
______ or ______ binds to GPCR and activates ______ ______ (which produces ______) –> cAMP activates ______ –> PkA inhibits _____ (by adding an inhibitor) and inhibits _____ (by phosphorylating) –> preventing assembling of glycogen (glycogenesis)
glucagon or epinephrine
adenylyl cyclase
cAMP
PkA
protein phosphatase 1 (PP1)
glycogen synthase
regulation of glycogenolysis by glucagon and epinephrine: glycogen phosphorylase activation:
______ or ______ binds to GPCR and activates ______ (which produces _____ ) –> cAMP activates ______ –> PkA phosphorylates and activates ______ which phosphorylates ______ and allows for _____ to take place
glucagon or epinephrine
adenylyl cyclase
cAMP
PkA
phosphorylase kinase (PK)
glycogen phosphorylase (is now activated)
glycogenolysis
regulation of glycogenolysis by glucagon and epinephrine:
net result:
glycogen breakdown (via inactivation of glycogen synthase and activation of glycogen phosphorylase)
glucagon does not act on
muscle cells
in liver, glucose 1-P converted to ______ and then to glucose by ______ which allows ______
glucose 6-P
glucose-6-phosphatase
free glucose to be released into blood stream
_______ _______ is considered the glucose sensor in liver cells
glycogen phosphorylase
GSD 0
defective enzyme:
pathway affected:
glycogen synthase
glycogenesis is affected
patients cannot synthesize glycogen
rely on glucose in diet
GSD 1
disorder name:
defective enzyme:
pathway affected:
Von Gierke disease
glucose 6-phosphatase
inefficient release of free glucose into the bloodstream by the liver in gluconeogenesis and glycogenolysis
GSD 2
disorder name:
defective enzyme:
pathway affected:
Pompe Disease
acid maltase (used in lysosomal glycogen degradation)
lysosomal glycogenolysis: accumulation of glycogen in lysosomes
progressive muscle weakness and myopathy (including heart and skeletal muscle)
ERT: recombinant human alpha-glucosidase delivered via IV infustion in children - effective
GSD 3
disorder name:
defective enzyme:
pathway affected:
Cori disease
debranching enzyme (alpha-1,6-glucosidase)
glycogenolysis: glucose cleavage and release from branch point
GSD 4
disorder name:
defective enzyme:
pathway affected:
anderson disease
glucosyl (4:6) transferase
glycogenesis: chain branching is limited
death by 5 years of age
GSD 5
disorder name:
defective enzyme:
pathway affected:
McArdle Disease
muscle glycogen phosphorylase
glycogenolysis: glucose 1-P release
muscles break down (myoglobin in urine)
GSD 6
disorder name:
defective enzyme:
pathway affected:
Hers disease
liver glycogen phosphorylase
glycogenolysis: glucose 1-P release
low blood glucose levels (fairly benign)
