Regulation of Glycogen Catabolism and Glycolysis Flashcards
Normal blood glucose levels?
3.6-5.8mM/L
-Hyperglycaemia if high
-Hypoglycaemia if low
What enzyme is regulated in glycogen catabolism?
Glycogen phosphorylase
(regulatory enzymes act on rxns that are irreversible)
What enzymes are regulated in Glycolysis?
The enzymes that catalyse the 3 irreversible exergonic steps
Enzyme step 1 - hexokinase
Enzyme step 3 - PFK-1
Enzyme step 10 - pyruvate kinase
How is glycogen phosphorylase turned on/activated?
Shape-shifting - allosteric regulation to turn on GP
-By phosphorylation on Serine 14 - creates more active form (phosphorylase a over phosphorylase b)
-Activated when GP binds AMP in muscle cells- low energy indicator
How do hormones cause the activation of glycogen phosphorylation at Ser 14?
GLUCAGON AND ADRENALINE
-When blood glucose is low both are released
-Glucagon acts on liver cells and adrenaline acts on skeletal muscle cells
-Both hormones bind to specific receptors to activate a signalling cascade that activates Protein Kinase A (PKA)
-Results in phosphorylation and activation of glucose phosphorylase - causes glycogen breakdown - glucose-1 phosphate production
How is glycogen phosphorylase turned off?
-When glycogen phosphorylase activity in liver has increased blood glucose to normal range (3.6-5.8mM/L) - glucagon and adrenaline are no longer released and AMP conc is no longer high in muscle
-Also when glucose conc is above 6.1mm/L in liver - 1 glucose binds onto each active enzyme subunit which causes phosphoryl groups to flick out and be cleaved off by phosphatase enzyme - this reshapes and inactivates GP enzyme
When blood glucose is high?
Insulin is released which is a major activator of GS (Glycogen synthase) and converts it to an active non-phosphorylated form
What are the isoenzymes of Hexokinase and where are these found?
4 isoenzymes (I-IV) - products of diff genes
HKI and II in all cells except liver
HK IV exclusive to liver and also called glucokinase
How is HK I-III vs HK IV regulated in liver?
HK I-III : much higher Km for glucose than HK IV
-HK I-III is half saturated at around 0.1mM glucose so these HKs work maximally with glucose conc coming in from blood range 3.5mM
-HK I-III enzyme activity inhibited allosterically by Glucose 6-P conc - when reaches high levels
-HK IV Km for glucose > 10mM
-Ensures lower glucose conc wont be catabolised maximally in liver but allowed to go to bloodstream to other tissues
-HK IV is not inhibited by high glucose 6-p conc
-HKIV - the liver form of HK is also inhibited by binding regulatory protein
How ia HK regulated by regulatory protein?
-When blood glucose conc is getting low <5mM hexokinase IV binds a regulatory protein which sequesters HK IV in nucleus
-So glycolysis in liver is not active in catabolisminh scarce glucose as HKIV is in the wrong location (in nucleus instead of cytosol)
-When glucose rises above 6mM- glucose blocks regulatory binding and HKIV enters cytosol so glycolysis is also used in the liver
How else are HKII and HKIV regulated?
Transcriptionally
-increases/decreases amount of HK synthesised as it is needed depending on energy demands
Levels of HK enzymes increase in cancer cells and certain immune cells
How is Phosphofructokinase-1 (PKA1) regulated?
-Allosterically and by hormone induced signalling/covalently
(catalyses step 3 of glycolysis, major regulatory enzyme of glycolysis “valve” and rate limiting step)
What causes the allosteric regulation of PFK-1?
-Activated by high conc of low energy indicators e.g AMP, ADP, fructose 2, 6 bisphosphate
-Inhibited by high conc of high energy indicators e.g ATP, citrate
What is the major allosteric activator of PFK-1 in the liver turning on glycolysis?
High Fructose 2,6-bisphosphate concentration
-Turns off glucogenesis as inhibits fructose 1,6 bisphosphatase-1 (FBPase-1) which converts Fructose 1,6-bisphosphate to fructose 6-phosphate in glucogenesis
How and why is fructose 2,6 biphosphate conc reduced in the liver?
-Reducing is v important in blocking glycolysus in liver when glucose conc is low
-Glucagon is released when glucose conc in low which binds to receptors on liver cells
-Glucagon signalling reduces Fructose 2,6 bisphosphate conc by phosphorylation and inactivation of its synthesising enzyme PFK-2
-Glycolysis in liver is stopped - glucogenesis is acrivated
How is Pyruvate kinase inhibited allosterically?
-Allosteric inhibition by high conc of high energy indicators e.g ATP, acteyl CoA, long chain fatty acids, alanine
-Allosteric activation by F16 bisphosphate
-Directly phosphorylated and inhibited via glucagon signal transduction in liver to stop glycolysis in liver when glucose conc is low
What isoforms does Pyruvate Kinase exist in?
PKM1 and PKM2
-exhibit differing rates of reaction
-under transcriptional regulation including in cancer
