Gluconeogenesis Flashcards
What does gluconeogenesis do?
Coverts non-carbohydrate substrates into glucose
What can the non-carbohydrate substances be?
pyruvate, lactate, glycogenic amino acids, TCA cycle intermediates, odd-chain fatty acids
In mammals when does gluconeogenesis work?
fasting or starving state
Where does gluconeogenesis operate?
in liver and sometimes kidney
Is gluconeogenesis the simple reversal of glycolysis?
no because glycolysis has 7 reversible reactions but 3 non-reversible reactions and converts phosphoenolpyruvate to pyruvate directly whereas gluconeogenesis converts pyruvate to oxaloacetate and oxaloacetate to phosphoenolpyruvate
What is the cori cycle?
The cycle where pyruvate is converted into glucose in the liver and is then transported in the blood to a muscle where it is converted into pyruvate. The pyruvate is then converted into lactate which is transported in the blood to the liver where it is converted to pyruvate
How is pyruvate synthesised from lactate?
using the enzyme lactate dehydrogenase and converting NAD+ to NADH
What is the structure of lactate?
H
I
HO-------------C---------------CH3
I
HO-------------C============OWhat is the structure of pyruvate?
Same as lactate except one OH group becomes =O
How is glycerol prepared to be used as a precursor in gluconeogenesis?
Hydrolysis of triglycerides by lipase in adipose tissue to produce glycerol and fatty acids
How does glycerol become involved in gluconeogenesis?
its converted into dihydroxyacetone phosphate and introduced into gluconeogenesis. (using. glycerol kinase to convert it into glycerol-3-phosphate and then glycerol phosphate dehydrogenase to convert it into DHAP)
What can’t be used as a precursor for gluconeogenesis?
fatty acids because fatty acid beta oxidation produces acetyl-CoA which cannot be directly converted to pyruvate by carboxylation
What happens when you use glycogenic amino acids as a precursor?
- Catabolism of these amino acids yields pyruvate or one of the intermediates of the TCA cycle
- These intermediates acts as a substrate for gluconeogenesis
What is the reaction converting pyruvate to oxaloacetate?
pyruvic acid + CO2 + H2O =oxaloacetic + Pi
using pyruvate carboxylase and ATP
How does the reaction converting pyruvate to oxaloacetate work?
- C terminal 80 amino acids constitute an amino acid binding site which acts as a carrier of activated carbon dioxide
- 3 stage process involving CO2 activation, followed by binding to a biotin binding site on enzyme followed by carboxylation of pyruvate
Where does the reaction converting pyruvate to oxaloacetate occur?
mitochondria
Oxaloacetate can’t be directly transported from the mitochondria to the cytosol, how does the transportation work?
- in the mitochondria oxaloacetate is reduced to malate (with production of NAD+)
- malate is transported to the cytosol where it is oxidised to oxaloacetate to produce NADH
How is oxaloacetic acid converted to phosphoenolpyruvate?
-It uses one GTP (donates P)
-PEP carboxykinase as the enzyme
and produces CO2
How do you convert fructose-1,6-biphosphate to fructose-6-phosphate?
- hydrolysis reaction of a phosphoric acid monoester (lose phosphate from 1 position)
- uses fructose-1,6-biphosphatase
What is the net reaction of gluconeogenesis?
2 pyruvate + 4ATP + 2GTP + 2NADH + 6H2O
glucose + 4ADP + 2GDP + 6Pi + 2NAD+ + 2H+
What is the net reaction of the reverse of glycolysis?
2 pyruvate + 2ATP + NADH + 2H2O
glucose + 2ADP + 2Pi + 2NAD+ + @H+
Does gluconeogenesis require the catabolism or anabolism of ATP?
Catabolism (breakdown)
Why does gluconeogenesis operate?
Loss of 6 high-phosphy-transfer metabolites are needed to turn an energetically unfavourable reaction into a favourable one
What drives the energetically unfavourable reactions in gluconeogenesis?
nucleoside triphosphate
What pathways are active and inactive when energy is needed?
- glycolysis active
- gluconeogenesis inactive
What happens when energy is in excess or not needed and biosynthetic intermediates are in excess?
gluconeogenesis is active
How are the pathways regulated so only glycolysis or gluconeogenesis is occurring at once?
- pathway enzymes are regulated to provide operation of one pathway only
- metabolites provide an inhibitory or stimulatory allosteric effect
(as there is no thermodynamic barrier to stop simultaneous operation)
What is the role of fructose-2,6-biphosphate?
- signalling molecule
- stimulates phosphofructokinase
- strongly inhibits fructose-1,6-biphosphate
What happens in low blood glucose levels?
- increase in hormone glucagon which signals a cyclic AMP signal cascade leading to phosphorylation by protein kinase A
- This activates FBPase2 and inhibits PFK-2 leading to a decrease in fructose-2,6-biphosphate, allowing glyconeogenesis to operate predominantly
What happens in high blood glucose levels?
- gluconeogenesis not needed
- insulin is secreted and initiates a signal pathway that activates a protein phosphatase which dephosphorylates the bifunctional enzyme
- this activates PFK and inhibits FBPase2 leading to an increase in fructose-2,6-biphosphate, allowing glycolysis to operate
What is glycogen?
storage form of glucose in mammals
Why is glycogen important for storage?
-high levels of glucose would disrupt osmotic balance and damage cells (glycogen not osmotically active)
Where is glycogen stored?
in the liver and skeletal muscles (also present in cytoplasm as granules)
What types of glycosidic bonds are there in glycogen?
- α-1,4-glycosidic bonds (lead to open helical polymers)
- α-1,6-glycosidic bonds (lead to branches)
What is the role of glycogen?
- used to provide glucose for ATP production
- fuel reserve
What is glycogenolysis?
when glycogen is enzymatically degraded to remove glucose units to produce glucose-1-phosphate
What does glycogenolysis catalyse?
phosphorolysis
what is the product of glycogen degradation?
α-D-glucose 1-phosphate
After glucose-1-phosphate is produced, what happens next?
it is enzymatically converted to glucose-6-phosphate by the enzyme phosphoglucomutase
What are the enzymes important in glycogen breakdown and production?
- glycogen synthase
- glycogen phosphorylase
What is glycogen phosphorylase regulated by?
- ATP (inhibition)
- glucose-6-phosphate (inhibition)
- AMP (activation)
When is glycogen phosphorylase active?
When its phosphorylated
How are GP and GS initiated?
through hormone triggered cyclic-AMP cascades
Where is insulin produced?
beta cells of pancreas
What does insulin do?
- increases the rate of glucose transport into cells/tissues via GLUT 4 transporter
- stimulates liver glycogen synthesis
Where is glucagon produced?
in the α cells of the pancreas
What is the role of glucagon?
- stimulates glycogen degradation
- only used in liver cells rich in glucagon receptors
What happens in Von Gierke disease?
the enzyme glucose-6-phosphase is defective
- can not release glucose from glucose-6-phosphate
- increased amount of glycogen
What are the symptoms of Von Gierke disease?
- enlarged liver through glycogen levels
- hypoglycaemia because glucose can not be released in fasted state
- ketosis as glucose-6-phosphate passes through glycolysis to produce high levels of pyruvate and lactate in the liver (released to blood)
- hyperlipidemia
- failure to thrive
What is the defective enzyme in cori disease?
amyloid-1,6-glucosidase (debranching enzyme)
causes increased amount of glycogen with shorter outer structure and produces milder forms of VGs
What is the defective enzyme in McArdle’s disease?
glycogen phosphorylase (can not release glucose from glycogen)
What is the effected organ in McArdle’s?
muscle
What effects does McArdle’s have?
increased amount of glycogen with a normal structure
