Regulation of Glycolysis Flashcards
What does Glycolysis convert?
One molecule of glucose into two molecules of pyruvate with the generation of two molecules of ATP
Where does Glycolysis occur?
- Glycolysis occurs in all tissues, particularly important for energy in brain and Rbc’s and also in contracting skeletal muscle
- Rbc’s account for 10%
of the total bodies usage
What are the two stages that Glycolysis can occur in ?
- Stage 1 = traps glucose in the cell and modifies it so that it can be cleaved into a pair of
phosphorylated 3-carbon compounds - Stage 2 = oxidises the 3-carbon compounds to pyruvate while generating two molecules of ATP
In the glycolytic pathway, metabolised glucose produces?
- ATP by substrate level and oxidative
- Glycerol-3-phosphate for fat synthesis
- Acetyl CoA for fat and cholestrol synthesis
- Amino acids
What is Fructose 1,6-bisphosphate generated from? (committed step of glycolysis)
Glucose 6-phosphate
Explain a little about the generation of Fructose 1,6-bisphosphate ?
The carbohydrate is trapped in the fructose form by the addition of a second phosphate to form fructose 1,-6 bisphosphate. This irreversible reaction is catalysed by the allosteric enzyme phosphofructokinase (PFK)
Major point of control lies at committed step of glycolysis, catalysed by ?
PFK1, a heterotetrameric enzyme: fructose-6-phosphate (F6P) and ATP are the substrates
What kind of kinetics does PK1 show ?
PFK1 shows sigmoidal kinetics: allosteric regulators bind at the interface between subunits of
the enzyme, shifting it between T and R states
What stimulates PKF1 and glycolysis ? and what inhibits it?
- Low energy charge (AMP, ADP) stimulates
- High energy (ATP) inhibits it
What are the other key regulators that inhibit and stimulate ?
Note other key regulators citrate (inhibits: signal of fatty acid oxidation) and fructose-2,6-bisphosphate (a pure regulator: activates)
What regulates the committed step of glycolysis?
Reciprocally regulated with fructose-1,6-bisphosphatase, which catalyses the reverse reaction (you lose a high energy phosphate to do this)
Purpose of Fructose 2,6 bisphosphate ?
Not involved in metabolic pathways, just a regulator: another product from F6P that acts solely to reinforce allosteric control on PFK-1
What does Fructose 2,6 bisphosphate activate and inhibit ?
- Activates glycolysis: strongest allosteric activator of PFK1
- Inhibits gluconeogenesis: strong inhibitor of fructose-1,6-bisphosphatase
What activates and inhibits PFK2 ?
Activated by:
- F-6-P
- AMP
- increases glucose concentration, glycogen breakdown (muscle) and contraction (low ATP)
Inhibited by:
- Citrate
- increases fatty acid oxidation (TCA cycle overload)
Explain the reciprocal control of committed step by
Fructose-2,6-bisphosphate?
- Glycolysis is accelerated by increased Fru-2,6BP by stimulation of PFK-1 and inhibition of Fru-1,6-BPase reducing futile cycling (increased glucose entry or, in muscle, glycogen breakdown)
- Glycolysis inhibited by decreased Fru-2,6BP by stimulation of Fru-1,6-BPase and inhibition of PFK-1 (reduced glucose entry or, in muscle, decreased glycogen breakdown)
Explain how F-2,6-BP is a problem in the liver ?
Liver: uses glucose produced via gluconeogenesis and glycogen to maintain blood glucose and glycolysis is inhibited – need to avoid F6P produced by gluconeogenesis leading to increased F-2,6-BP levels
Explain the the bifunctional enzyme in the liver ?
In liver, not only have to control glycolysis at the level of PFK-1, but also the reverse reaction of gluconeogenesis at F-1,6,BPase to allow reciprocal control of the two reactions
What kind of enzymes are PFK-2 and F-2,6-BPase in the liver ? and how are they controlled ?
They are a single tandem enzyme with two active sites:
• N-terminal kinase domain
• C-terminal phosphatase domain
- These are controlled hormonally via phosphorylation
What does the Hormonal regulation of glycolysis and gluconeogenesis depend on?
The phosphorylation state of
PFK-2/FBPase-2
What does Insulin signalling activate ?
It activates the PFK-2 domain, increasing glycolysis
What does Glucagon signalling activate ?
The FBPase-2 domain, increasing gluconeogenesis
High glucose which leads to high F6P, stimulates and inhibits ? (liver)
- Stimulates PFK2
- Inhibits F-2,6-BPase
Citrate spilling out of the mitochondria during acetylCoA overload (e.g. starvation) will ?
Inhibit PFK2 (and PFK1): promote gluconeogenesis
What is PEP and what does it inhibit ?
- PEP, one of the first products of gluconeogenesis
- Inhibits PFK2
