Metabolic Regulation and Control Flashcards
What happens if there is too little glucose in blood supply?
brain problems (<5mM)
What happens if there is too much glucose in blood supply?
osmotic water loss and damaged blood vessels
What hormone is released to buffer against a high conc of glucose in the blood?
Beta sells release insulin
What hormone is released to buffer against a low conc of glucose in the blood?
Alpha sells release glucagon
What happens after the release of insulin?
- increase rate of glucose transported into cell
- increased rate of glucose utilisation and ATP generation
- inc conversion of glucose to glycogen
- inc protein synthesis
- inc fat synthesis
blood glucose conc decline and homeostasis is restored
What happens after the release of glucagon?
- increased breakdown of glycogen to glucose
- increased breakdown of fats to fatty acids
- inc synthesis and release of glucose
What is the flow of metabolism determined by?
The amount and activity of enzymes
What is homeostasis?
The maintenance of an internal environment
What happens during a steady state rate?
- maintaining of homeostasis
- rate of synthesis of a metabolite equals its rate of conversion to product
- all enzymes in a pathway operate at the same net rate
What is the net flow of the typical metabolic pathway?
- reactions will all operate near equilibrium
(A->BCDE) - Any small change in conc of metabolite which affects the net rate
- e.g. if increase of [B], rates of reaction will change so that it will make more of C to lower the [B] to make it back to the equilibrium
What is the Keq and Mass Action Ratio of the typical metabolic pathway?
Keq and MAR are close (0-100)
What is a FAR-from equilibrium reaction?
- an irreversible reaction
- ΔG «_space;0
- e.g. PFK1
- slow rate
- changes in [substrates] have little effect on the reaction
- only changes in enzyme activity (allosteric interactions) can significantly alter the rate
What is the Keq and Mass Action Ratio of a FAR-from equilibrium reaction?
MAR «< Keq
Give an example of an enzyme with a FAR-from equilibrium reaction.
PFK-1
- F6P + ATP -> F1,6BP + ADP
- 3rd step of glycolysis
- insufficient activity, too few molecules of PFK1 present and activity limited by effectors
- rate of reaction is too slow to allow reaction to approach equilibrium
Which type of equilibrium is the control point?
The FAR-from equilibrium reaction is the control point
Why is the rate determining step hypothesis proved to be wrong?
- because the net rate is the same
- found contradictory results during genetic engineering experimental findings
- too simplistic a view
What is the rate determining step hypothesis?
The RDS enzyme was expected to:
- occur at the beginning of a pathway or at branch points
- have low activity overall
- catalyse a non-equilibrium reaction
- be allosteric (subject to feedback inhibition, covalent modification)
What is metabolic regulation?
- processes that maintain homeostasis at molecular level
- hold the concentration of a metabolite at a steady level over time
State an example of regulation vs control of glycogen synthesis from blood glucose.
Regulation:
- insulin activation of Glycogen synthase by phosphorylation cascade prevents major changes in G6P levels
Control:
- insulin increases in uptake of glucose into cells (GLUT4) and synthesis of Hexokinase to increase flux towards glycogen
How was the testing of the single RDS (Rate determining step) hypothesis conducted?
- genetic engineering experiment
- increase the amount of the RDS enzyme to see if the flux would increase proportionately
- saw that hexokinase increased glycolytic rate much more than PFK-1 did (rat liver)
- in yeast, increasing PFK1 by 5 produced <10% increase in flux through glycolysis
What did the engineering experiment to test the RDS hypothesis show?
- in most pathways, the control of flux is distributed over several enzymes
- PFK1 regulation is not to control glycolytic flux but to produce metabolic homeostasis
What is the most effective way to increase metabolic flux?
The Metabolic Control Analysis predicts that you can do this by raising the concentration of all enzymes in a pathway
What is a substrate cycle?
2 or more enzymes catalyse opposing reactions
- one usually requiring ATP
- they may amplify metabolic signals (with modest changes in rate of enzymes) and stimulate flux through a pathway
State an example of reciprocal regulation of glycolysis and gluconeogenesis by substrate cycle of PFK1 and FBP.
- Both enzyme have allosteric controls that ensure both reactions do not occur fully simultaneously (e.g, inc in AMP and decrease in Citrate promotes PFK1 whereas does opposite to FBP)
- some glycolysis can happen during gluconeogenesis
- important in Bumble bees to maintain temperature to inc glycolysis (generating heat) during gluconeogenesis
