gluconeogensis (GNG) Flashcards
Gluconeogensis
metabolic pathway that results in the generation of glucose from non-carbohydrate presursors
purpose of gluconeogensis
maintain blood glucose levels and avoid hypoglycemia under conditions of fasting (10-18 hours)
What two tissues can synthesize glucose?
liver and kidney cortex
What tissue does GNG primarily take place in?
liver
When does GNG happen in kidney cortex?
only during prolonged fasting, contributes up to 40% of the total glucose production
subcellular localization
- step 1 in mitochondrial matrix
- cytosol (all reversible steps of glygolysis)
- ER (last step [dephos] to produce glucose
substrates for gluconeogensis
- glycerol
- amino acids (AA)
- lactate
- Acetyl CoA
glycerol as substrate in GNG
-released during hydrolysis of TAGs in adipocytes and is delivered by the blood to the liver
-adipocytes lack glycerol kinase
- in the liver
glyverol—glycerol-phosphate—–DHAP
amino acids as substrate in GNG
- major source are derived from tissue protein hydrolysis
- very late in starvation mode, after all fat is gone
- most AA converted in TCA to intermediates that yield OAA at some point
lactate as substrate in GNG
- converted back into pyruvate in the liver by lactate dehydrogenase
- released from cells under anaerobic conditions
- Cori cycle
Cori Cycle
glucose converted into lactate under anaerobic glycolysis, excreted to plasma and sent to the liver to be converted back to glucose and released into circulation
Acetyl CoA as substrate in GNG
- CANNOT be converted to pyruvate in humans
- PDH is irreversible and there is NO enzyme for the reverse reaction
- FA cannot serve as substrate (only glycerol)
- FA oxidation provides energy to liver required to perform GNG
how many reversible reactions of GNG are there?
7
highly dependent on cxn of products and substrates
how many irreversible reactions of GNG are there?
3
overcome by using 4 alternative enzymes
4 alternative enzymes used to overcome the 3 irreversible steps
1. pyruvate---OAA Pyruvate carboxylase 2. OAA---PEP PEP carboxykinase 3. F-1,6-bis-P-----F-6-P F-1,6 bisphosphatase 4. G-6-P----glucose Glucose 6 phosphatase
- carboxylation of pyruvate to OAA
- unique to GNG
- mitochondrial matrix
- provide OAA for GNG and TCA replenishment
- enzyme: pyruvate carboxylase, malate dehydrogenase, PEP carboxylase
- OAA cannot be exported (lack of transporter)
- converted to malate
- M exported and converted back to OAA
pyruvate carboxylase
- enzyme for first step of GNG
- requires biotin as a coenzyme
- allosterically activated by acetyl CoA
why can OAA not be exported?
lack of transporters , has to be converted to malate
- decarboxylation of cytosolic OAA
- IRREVERSIBLE
- driven by GTP hydrolysis
- pairing carboxylation with de-carboxylation makes GNG energetically possible
- enzyme: PEP-carboxykinase (PEPCK)
What makes GNG energetically possible?
decarboxylation of cytosolic OAA
- dephosphorylation of fructose 1,6-bis-P
- hydrolysis reaction
- bypasses the irreversible PFK-1 reaction
- important site for regulation
- enzyme: fructose 1,6-bisphosphatase
fructose 1,6-bisphosphatase
- dephosphorylation of fructose 1,6-bis-P
- inhibited by AMP and allosterically by fructose 2,6 bis-P
- activated by high ATP, low AMP
regulation by fructose 1,6-bisphosphate
- synthesized by PFK-2
- inactivates fructose 1,6-bisphosphatase and stops GNG
- commone regulator allows tight regulation assuring the pathways of glycolysis and gluconeogensis are mutually exclusive
- dephosphorylation of glucose 6-P
- hydrolysis reaction
- bypasses the irreversible hexo/glucokinase reaction
- provides energetically favorable step to produce glucose
- enzyme: glucose 6-phosphatase
