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
glucose 6-phosphatase
- enzyme for dephosphorylation of glucose 6-phosphatase
- also used during glycogenolysis to yield free glucose
- glucose can then be transported out of the liver to maintain blood glucose
gluconeogenesis summary
-endergonic
-anabolic
-per 1 glucose
4 ATP and 2 GTP are used
2 NADH are used
regulaltion by glucagon
- inhibits PFK-2, lowers fructose 2,6-BP inhibiting glycolysis and activating GNG
- inhibits pyruvate kinase, therefore PEP is used for GNG as opposed to glycolysis
- stimulates transcription of PEPCK, insulin inhibits it
regulation by substrate availability
- protein breakdown in other tissues and subsequent amino acid release yields gluconeogenic precursors in the liver, which stimulate GNG
- ATP and NADH are provided by the oxidation of FA in the liver
allosteric activation by ACetyl CoA
- buildup of acetly CoA, signals the diversion of OAA for GNG
- activates pyruvate carboxylase
- inhibits PDH, assuring pyruvate is diverted to the production of glucose and away from the TCA cycle
allosteric inhibition of AMP
- F1,6BP inhibited by AMP
- PFK-1 activated by AMP
- as with regulation of the two enzymes by fructose 2,6-BP, the reciprocal regulation of each of these enzmyes by the same allosteric effector assures the two pathways are mutually exclusive
regulation of GNG
- regulation by glucagon
- regulation by substrate availability
- allosteric activation by acetyl CoA
- allosteric inhibition by AMP
What ensures that glycolysis and gluconeogensis are mutually exclusive?
- regulation by fructose 2,6-BP
- allosteric inhibition by AMP
