Gluconeogenesis Flashcards
Gluconeogenesis
A metabolic pathway that results in the generation of glucose from non-carbohydrate precursors
Purpose of GNG
To maintain blood glucose levels and avoid hypoglycemia under conditions of fasting (>10-18 h)
Tissues involved in GNG
Liver
-predominantly ~90% in overnight fast
Kidney Cortex
~10%
-only during prolonged fasting will it near 40%
Subcellular localization of GNG
Mitochondrial matrix - step 1
Cytosol - all reversible steps of glycolysis
ER - last step (dephosphorylation) to produce glucose
Substrates of GNG
Glycerol, Amino Acids, Lactate, Acetyl CoA
Glycerol 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:
Glycerol -> glycerol-phosphate -> DHAP (glycolic intermediate)
Adipocytes lack _______ _____, which is why it is transferred to the liver.
Glycerol kinase
Amino Acids in GNG
Major source of AA are derived from tissue protein synthesis
Ala is the major AA used but 18 out of 20 can be used
Most of the AA are converted in the TCA to intermediates that can yield OAA at some point
What is the major AA used in GNG?
Alanine
But others can be used
Lactate in GNG
Can be converted back into Pyruvate by Lactate Dehydrogenase
Released from cells under anaerobic conditions (RBCs and exercising muscle)
What enzyme converts lactate back into Pyruvate?
Lactate dehydrogenase
What does the Cori Cycle do?
Converts glucose into lactate (under anaerobic conditions)
Excretes lactate to plasma and then sent to the liver
Lactate is then converted back into Glucose
Released back into circulation (to be possibly repeated)
FORMS A CYCLE YO
Acetyl CoA in GNG
Cannot be converted back into Pyruvate in humans
PDH is irreversible and there is NO enzyme for the reverse reaction
Fatty Acids CANNOT serve as a substrate for Gluconeogenesis
FA oxidation provides the liver with the energy requires to perform Gluconeogenesis
How is Acetyl CoA converted back into Pyruvate in humans?
It’s not. It can’t. Idiot.
__________ cannot serve as a substrate in Gluconeogenesis.
Fatty Acids
____ ____ ________ provides the liver with energy requires for perform GNG.
Fatty Acid Oxidation
How many reversible and irreversible reactions are in GNG?
7 reversible
3 irreversible
11 total
Gluconeogenesis is the opposite of….
Glycolysis
The irreversible steps are due to 4 alternative enzyme in what UNIQUE steps?
- Pyruvate to OAA
- OAA to PEP
- F-1,6-bis-P to F-6-P
- G-6-P to Glucose
Carboxylation of Pyruvate to OAA
In the mitochondrial matrix
Provide OAA for GNG and TCA replenishment
Enzyme: Pyruvate Carboxylase
- Requires biotin as a coenzyme
- Allosterically activated by Acetyl CoA
OAA cannot be exported, so converted to Malate, then converted to OAA once exported
Enzymes: Malate dehydrogenase and PEP carboxykinase
Pyruvate Carboxylase requires _____ as a coenzyme and is allostericall at activated by ______ ___.
Biotin, Acetyl CoA
The Carboxylation of Pyruvate to OAA takes place in the…
Mitochondrial matrix
Oxaloacetate is exported to the cytosol by…
Due to the lack of transporters for OAA, it is converted to Malate, then transported.
Once in the cytosol, it is converted back into OAA.
-via PEP carboxykinase and Malate dehydrogenase
Decarboxylation of cytosol in OAA
IRREVERSIBLE
Driven by GTP hydrolysis
Pairing Carboxylation with de-carboxylation makes GNG energetically possible.
Enzyme: PEP-carboxykinase (PEPCK)
Dephosphorylation of F-1,6-bisP
hydrolysis reaction
Bypasses the irreversible PFK-1 reaction
Important site for regulation
Enzymes: F-1,6-bisphosphatase
- Inhibitors: AMP (signal energy poor=stop), and allostericall you by F-2,6-bisP
- Activators: high ATP, low AMP
Regulation by fructose-2,6-bisphosphatase (synthesized by PFK-2)
inactivates f-1,6-bisP and stops GNG
The common regulator allows tight regulation assuring the pathways of glycolysis and Gluconeogenesis 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
- also used during Gluconeogenesis to yield free glucose
- glucose can then be transported out of the liver to maintain blood glucose
Summary of GNG
endergonic (Energy-requiring), anabolic
For 1 Glucose:
4 ATP used
2 GTP used
2 NADH used
Regulation of GNG by glucagon
Inhibits PFK-2, lowers f-2,6-bisP inhibiting glycolysis and activated GNG
Inhibits Pyruvate kinase, therefore PEP is used for GNG as opposed to glycolysis
Stimulates transcription of PEPCK, insulin inhibits it
Regulation of GNG by substrate availability
Protein breakdown in other tissues and subsequent AA release yields gluconeogenic precursors in the liver, which stimulate GNG
ATP and NADH are provided by the oxidation of FAs in the liver
Allosteric activation by Acetyl CoA
Buildup of Acetyl CoA, signals the diversion of OAA for Gluconeogenesis
Activates Pyruvate Carboxylase
Inhibits PDH, assuring Pyruvate is diverted to the production of glucose and away from the TCA cycle
Allosteric inhibition by AMP
F-1,6-bisP is inhibited by AMP
PFK-1 is activated by AMP
As with regulation of the two enzymes by F-2,6-bisP, the reciprocal regulation of each of these enzymes by the same Allosteric effector assures the two pathways are mutually exclusive
