Summary of Metabolic control

Control of Glycolysis
Regulated to meet cellular needs
In muscle: lots of ATP is needed e.g. for
fight or flight response
In liver: buffers blood glucose doesnt
use a lot of ATP but produces lots of
glucose
Enzymes are the only things that will slow
the reactions down
Can be controlled at different stages:
Phosphofructokinase -1
Most important controller of the
glycolytic pathway
Phosphorylates fructose-6-phosphate
In muscle:
Tetramer
Phosphorylates Fructose-6-phosphate
Inhibited by ATP
Feedback inhibition inhibition by
final products
When the cell no longer needs
energy
Prevents glucose being turned into
pyruvate so its used for
glycogenesis
Inhibited by low pH levels i.e. due to
lactic acid build up
Prevents cells from anaerobically
respiring too much which would
cause damage

Activated by fructose-2,6bisphosphate
Produced by phosphorylation of
excess fructose-6-phosphate by
PFK-2
Feed-forward inhibition
When theres excess glucose,
glycolysis needs to speed up
Insulin will activate PFK-2
Glucagon will deactivate PFK-2
Activated by AMP
When the concentration of ATP is
low glycolytic pathway is
stimulated

The liver is special

High levels of citrate are also needed
for ATP to inhibit pathway
Low Fructose-6-phosphate (and
therefore low fructose-2,6bisphosphate) causes gluconeogenesis

Hexokinase
Inhibited (heterotrophically) by
glucose-6-phosphate
When lots of ATP has been made,
muscle cells will stop glycolysis
The Liver is special (again)
Liver cells use glucokinase (an
isoenzyme)
Has a higher Km so tolerates more
glucose
Important because the GLUT2 channels
are non-insulin responsive
The enzyme would constantly be
inhibited

Inhibition is by a regulatory protein

Anchors glucokinase into the
nucleus to stop it interacting with
glucose
Regulator binds tighter when theres
more fructose-6-phosphate in the cell
Stops the liver using up all the
glucose

Activated by high concentration of

glucose in blood e.g. after a meal
Glucose will diffuse into cell and
counteract effects of F-6-P
Glycolysis continues when blood
glucose is high

Not controlled by G6P so will still

make it for glycogenesis when glucose
concentration is high

Pyruvate Kinase
Activated by fructose-1,6bisphosphate
Feed forward mechanism
Inhibited by high concentrations of
ATP, acetyl-CoA, and long-chain fatty
acids
Stops the glycolysis when energy
levels are high in the cell
In the liver
Inhibited by phosphorylation (by
PKA)
Under the action of hormones e.g.
Glucagon
Stops the liver using the glucose
when other organs need it

Controlling Glycogen Metabolism

Control is though hormonal and electrical responses
E.g. When blood glucose levels are low cAMP cascade is initiated
cAMP activates protein kinase A
This phosphorylates phosphorylase kinase and glycogen synthase
Glycogen synthase
Can be inactivated by phosphorylating its sites
Glycogen Phosphorylase B (inactive state)
Activated by phosphorylating its sites at Ser14
Causes basic residues at amino terminal to move out of the acidic
environment and into an active conformation
Using enzyme Phosphorylase Kinase
Activated by Ca2+ in muscle
Can also be allosterically activated using 5 AMP
Inhibited by ATP and Glucose-6-P
Stops you making breaking down glycogen while making it
Inhibited by dephosphorylating its sites
Using enzyme Phosphorylase phosphatase
Control of Gluconeogenesis
Fructose-2,6-Bisphosphate
Remember this only occurs in the liver
Activates PFK-1
Inhibits FBPase-1

Produced by phosphorylation of excess fructose-6-phosphate by PFK-2

Feed-forward inhibition
When theres excess glucose, glycolysis needs to speed up

Insulin will activate PFK-2

Causes an increase in glycolysis and a decrease in gluconeogenesis to
lower blood glucose levels
Glucagon (and adrenaline) will deactivate PFK-2
Causes an increase in gluconeogenesis
Leads to an increase in blood glucose levels

Pyruvate carboxylase
Activated by acetyl-CoA and FBP-1
Increases conversion of excess pyruvate back into glucose

Controlling the citrate cycle

Must be tightly controlled
Once things enter this cycle theres no going back (you gate get the glucose)
Acetate cant be turned back into pyruvate
ATP, NADH are used to regulate enzymes in both reactions to ensure levels
match
Regulation is by: Feedback inhibition, Product accumulation, substrate
availability
1) Pyruvate dehydrogenase (PDH)
Catalyses the reaction from pyruvate to acetate
Inhibited by covalent modification
Due to phosphorylation by PDH kinase
PDH Kinase is inhibited by pyruvate
PDH Kinase is activated by ATP
Lots of pyruvate = more citrate = more glycogenesis

Can be activated by dephosphorylation

Due to PDH Phosphatase
PDH phosphatase is activated by Ca2+ and insulin
Required during exercise and feeding

Activated by AMP, NAD+ & CoA

They accumulate when too little acetate is in circulation
Inhibited by presence of lots of Acetyl CoA, ATP & NADH
Feedback inhibition
Enzyme monitors of AMP:ATP and CoA:Acetyl CoA

2)

Citrate synthase
Limited by availability of substrate
Inhibited by ATP
When its inactive, oxaloacetate used to start gluconeogenesis
Acetyl CoA used to generate ketone bodies

3) Isocitrate dehydrogenase
Inhibited by high NADH/NAD+ ratio and ATP
Stimulated by ADP
4) ketoglutarate dehydrogenase
Inhibited by NADH and product (succinyl-CoA)

Regulation of Fatty acid oxidation

Using TAG lipase
Activated by PKA due to adrenaline, noradrenaline and glucagon
Phosphorylates it
Insulin inhibits it by promoting phosphodiesterase that break down cAMP
Starvation & use of Glycerol
When your blood glucose concentration is low, theres no insulin in your
blood
This means there arent GLUT4 transporters in membrane of adipocytes
Less glucose is taken up
Adipocytes rely on glycerol as a source of glucose
Fatty acids cant be re-esterified
They are released from adipocytes
Transport into mitochondria
Manoyl CoA can inhibit the carnitine shuttle in the liver
Produced during synthesis so youre not synthesizing and degrading at the
same time
Availability of NAD and FAD
If theres competition with the Krebs Cycle, fatty oxidation will lose
Hydroxyacyl CoA dehydrogenase is inhibited by high NADH/NAD ratio
Regulation of Fatty Acid Synthesis
Acetyl CoA Carboxylase 2
Catalyses the rate limiting step of the reaction
Activated by high citrate levels
This will also inhibit PFK-1
Activated by insulin
Leads to an increase in manoyl CoA levels
Inhibited by Glucagon and adrenaline
Trigger its phosphorylation
Inhibited by Acyl CoA it so fatty acids arent over produced
Glucose uptake is tightly controlled
This affects acetate levels
Control of Triacylglycerol production
3 Fatty acyl CoA + glycerol-3-phosphate TAG
Relies on constant glycerol-3-phosphate supply
Insulin increases activity of enzymes that add acyl groups to glycerol
Insulin stimulates production of glycerol from glucose
A long-term high carbohydrate diet will indirectly increase the production of
NADPH