Gluconeogenesis Flashcards
When do we need gluconeogenesis?
In exercise- when lactate is produced this can be converted to glucose
- Short term fasting- intermediates of carb synthesis (oxaloacetate / pyruvate) –> aa e.g. alanine (aa)–> glucose
- Diabetes- ironically gluconeogenic pathway turned on although blood glucose levels in blood are high not detected by liver cells believe insufficient glucose in cell
Leads to more glucose pumped into blood–>exacerbate hypoglycaemia as cells not taking glucose up
- Trauma- insulin receptors don’t get to surface as well as they should- hence gluconeogenesis stimulated
How much glucose is required?
• Glycogen levels run out 12 hrs after ingestion
• After this there is an increase in the gluconeogenic pathway
• This will last a few days
• In starvation conditions (where haven’t eaten for a few days) we still have some gluconeogenesis but also switch to fat metabolism
And we have ketone body formation
- enough glycogen stores to last about 1 day
What cells prefer glucose as substrate
- Brain and RBC (as no mitochondria so no oxidative phosphorylation- need glucose for glycolysis)
What molecules go through gluconeogenic pathway?
- Lactate (–> glucose)
- aa e.g. alanine
- Triglycerides form adipose tissue break down (glycerol–> gluconeogenic pathway and free fatty acids- B-oxidation pathway)
Which tissues undergo gluconeogenesis?
- Liver (main tissue)
- Kidney
- Small intestine
Where does this take place and why?
- cytosol- as most enzymes same as those for glycolysis
Explain pathway
- Reversal of glycolysis
- Except for 3 steps:
Pyruvate–> PEP
Fructose 1,6 bisphosphate–> F6P
G6P–> Glucose
Explain in further detail 1st step that differs to glycolysis in gluconeogenic pathway
- pyruvate–> PEP (2-phosphoenolpyruvate) in the MITOCHONDRIA-
pyruvate +CO2 +ATP–> oxaloacetate + ADP + Pi - via pyruvate carboxylase (mito.)
- requires CO2 and cofactor biotin (B6)
- oxaloacetate converted to malate
oxaloacetate+ NADH + H+–> NAD+ + malate (malate shuffle) - Malate passes out of nitochondria
- once in cytosol using NAD+ back to oxaloacetate
- oxaloacetate + GTP–> PEP + GDP +CO2 via PEP carboxylase
- super mouse if PEP in XS
Why is pyruvate carboxylase useful?
- Found in all tissues
- antipleuritic reaction (restoring intermediates- in this case of the TCA cycle)
- Forms oxaloacetate from pyruvate
- oxaloacetate needed to form a-ketoglutarate, isocitrate etc
Explain in further detail 2nd step that differs to glycolysis in gluconeogenic pathway
fructose 1,6 BP to fructose 6 phosphate via fructose 1,6- diphosphatase
- reciprocal regulation with glycolysis enzyme phosphofructokinase
- fructose 1,6-biphosphate +H2O–> fructose 6-phosphate +Pi
(imagine P group being replaced by OH)
Explain in further detail 3rd step that differs to glycolysis in gluconeogenic pathway
- G6P + H2O–> glucose +Pi
imagine P being replaced by OH
Overall reaction
2 pyruvate +4ATP +2GTP +2NADH +6H2O–> glucose +4ADP +2GDP+ 8Pi +2NAD +2H+
Outline how glycolysis and gluconeogenesis is controlled
- allosteric effectors
- hormonal regulators
What are allosteric regulators of glycolysis/ glycogenolysis
Glycolysis- phosphofructokinase: activated by F2,6-BP, AMP
Inhibited by citrate, H+ and ATP
Gluconeogenesis: instead inhibited by AMP, F2,6- BP
activated by citrate
Also inhibition/ activation going from pyruvate to phosphoenolpyruvate
Hormonal regulation of gluconeogenesis/ glycolysis
- Insulin- promotes synthesis of glycolytic enzymes (phosphofructokinase- fructose-6P–> fructose 1,6-BP)
Also inhibit synthesis of PEPCK- phosphoenolpyruvate carboxylase (oxaloacetate–> phosphoenolpyruvate) REM pyruvate–> oxaloacetate via pyruvate carboxylase - Glucagon- increases expression PEPCK and F1,6BPase
What is the cori cycle?
- In muscle pyruvate converted to lactate in anaerobic respiration via lactate dehydrogenase
- Travels in bloodstream to liver lactate–> pyruvate–> glucose
- In liver many gluconeogenic enzymes
- Including LDH in different isoform which can bind lactate
- this can go back in blood to brain or to muscle
How can aa be used as gluconeogenic precursors
- remove amino group
- carbon skeleton converted to glucose
- transamination reaction
e. g. alanine can have amino group removed to get pyruvate, then can be converted to oxaloacetate (via pyruvate carboxylase) and join gluconeogenic pathway
Explain how glycerol can be used as a substrate for gluconeogenesis
Formed from breakdown adipose tissue
- Triacylglycerol–> FFA (free fatty acids)+ glycerol
- Glycerol used as substrate but not fatty acids
- Glycerol–> DHAP (dihydroxyacetone phosphate)–> glyceraldehyde 3-phosphate via triose isomerase and back into gluconeogenic pathway
Why would a large alcohol intake lead to hypoglycaemia and ketoacidosis?
- Removing alcohol requires NAD+ to form a lot of NADH
- NAD+ needs to be regenerated via pyruvate–> lactate pathway
- Hence elevated lactic acid in individual
- OR get NAD+ from oxaloacetate–> malate
- depletes stores pyruvate and oxaloacetate both needed for gluconeogenic pathway
