Regulation: Glycolysis Flashcards
What are the enzymes which regulate glycolysis?
Hexokinase (1) PFK 1 (3) Pyruvate kinase (10)
What happens when hexokinase attaches to glucose?
Large conformational change observed when it clamps down of glucose.
Pacemaker of glycolysis.
How many isoenzymes are there of hexokinase?
4 - in mammals products of different genes.
Which hexokinase isoenzymes are in all cells except for the liver?
HK(I) and HK(II) and III
Which hexokinase isoenzyme is exclusive to the liver?
HK (IV) = glucokinase
What does HK (I-III) have a higher of than HK (IV)?
HK (I-III) has a higher Km for glucose than HK IV and is half saturated at 0.1mM of glucose.
When do HKs work maximally?
When coming in from a blood range of 3-5mM ex: in muscle.
How are the HK(I-III) inhibited and by what?
Inhibited allosterically by G6P its product when G6P reaches high concentrations.
What does HK (IV) ensure that lower glucose won’t be metabolised maximally in liver but allowed to go out into the bloodstream to other tissues?
The Km is always greater than 10mM
Is not inhibited by high glucose G6P.
How is HK IV inhibited ?
By the binding of a regulatory protein - when blood glucose is low (<5mM) it binds to a regulatory protein which sequesters HK in nucleus.
What happens when glucose rises in the liver cell?
6mM glucose blocks regulatory binding & HK (IV) and it enters the cytosol.
Downstream regulators enhance this.
HK (II and IV) are also regulated transcriptionally increased/decreases amount of HK synthesised as it is needed depending on the energy depends.
What is the valve of glycolysis?
Phosphofructokinase- 1 (PFK-1)
Rate limiting step - regulated allosterically and by hormone induced signalling/covalently.
What are the on switches for PFK-1?
AMP, ADP
Fructose 2, 6 - bisphosphate (activator in liver)- conversely inhibits fructose 1, 6- bisphosphate= turns of gluconeogenesis.
What are the off switches of phosphofructokinase -1?
ATP
Citrate
Which organ is the most important in terms of glucose metabolism timing?
Liver
What determines the cellular concentration of fructose 2, 6 biphoshphate?
The rates of synthesis by the enzymes which make and break it.
If glycolysis is stimulated what is inhibited?
Gluconeogenesis.
In the liver what regulates PFK2 and FBPase reciprocally?
Glucagon released when glucose levels are low.
Insulin is released when glucose levels are high.
What is achieved by glucagon in the liver?
It is released when the glucose is low, bind receptors on liver cells. Glucagon signalling reduces fructose 2, 6 bisphosphate by phosphorylation and inactivation its synthesising enzyme PFK-2.
Glycolysis stops
How is pyruvate kinase regulated/inhibited?
Allosterically by high concentrations of high energy indicators.
- ATP, acetyl CoA
- long chain fatty acids.
-alanine
allosteric activation by F1, 6- bisphosphate.
How is pyruvate kinase inhibited/activated?
Direct phosphorylation and inhibition via glucagon signal transduction in live to stop glycolysis in liver when glucose is low.
What are the two isoforms of pyruvate kinase?
PKM1 and PKM2
How are the isoforms of pyruvate kinase exhibited?
Through differing rates of reaction.
Under transcriptional regulation including in cancer.
What other cells besides hepatocytes have receptors for glucagon?
Adipocytes - glucagon mobilises the breakdown of fats for energy as glucose is not being used.
Where are the receptors mainly for adrenaline?
Skeletal and fat cells.
Adrenaline is released when?
Low blood glucose and fight/flight
- in muscle increases glycogen breakdown but unlike liver glucose for energy in the muscle cells so increase glycolysis.
Which organ turns on/off glycolysis and gluconeogenesis?
Liver
When is insulin released?
When blood glucose is high
Where are the insulin receptors?
Liver, fat, muscle and other cell.
What does insulin do?
It increases glucose uptake into cells and through glucose transporter proteins.
- increase glycogen synthesis in liver and muscle.
How does insulin increase glycogen synthesis?
Dephosphorylating glycogen phosphorylase -> no glycogen catabolism
Activating the glycogen synthase enzyme.
What is the product of insulin increasing glycogen synthesis?
glycolytic enzyme activity and acetyl coA production in liver
What can acetyl coA be used for other than glycolysis?
For fatty acid synthesis in the liver and transported to adipocytes where fatty acids converted to triacylglycerol.
