GNG Flashcards
Gluconeogenesis
- GNG
- Metabolic pathway that results in the generation of glucose from non-carbohydrate precursors
- Anabolic
GNG purpose
-to maintain blood glucose levels and avoid hypoglycemia under conditions of fasting(more than 10-18 hours)
What organs is GNG?
- Liver:predominantly
- Kidney cortex: at lesser extent, only during prolonges fasting contribute up to 40% of total glucose production
Where in cell is GNG?
Step 1: mitochondrial matrix
Middle steps: all reversible steps of glycolysis
Last Step: ER
Substrates for GNG
glycerol
- AA
- lactate
Glycerol
- release during hydrolysis of TAGs in adipocytes and is delivered by the blood to liver
- adipocytes lack glycerol kinase
- only in the liver: glycerol—>glycerol P—>DHAP
Amino Acids
- major source are AA derived from tissue protein hydrolysis(use muscle mass in times of starvation)
- Alanine is major AA used, but most can be
- Most AA are converted in the TCA to intermediates that can yield OAA at some point
Lactate
-can be converted back into pyruvate in the liver by lactate dehydrogenase(enzyme is only in the liver. lactate from RBC to liver to be converted and avoid build up)
Cori Cycle
- -glucose converted into lactate under anaerobic glycolysis
- excreted to plasma
- sent to liver to be converted back to glucose
- released back into circulation
Acetly CoA
- CANNOT BE CONVERTED TO PYRUVATE IN HUMANS
- PDH is irreversible
Fatty Acids
- FA cannot be used as substrate for GNG
- FA oxidation provides the liver with the energy required to perform GNG
reversible steps of GNG
- 7 reversible steps from glycolysis
- highly dependent on concentration of substrates and products
Carboxylation of pyruvate to OAA(part 1)
- in mitochondrial matrix
- provide OAA for GNG and TCA replinishment
- pyruvate can’t go into mitochondria
- requires Biotin as coenzyme
- allosterically activated by acetyl CoA
Biotin/Bicarbonate
- biocarbonate ion is not free floating, attached to CO2
- biotin is bound to pyruvate carboxylase so biocarbonate ion can attach and release C for pyruvate
Carboxylation of pyruvate to OAA(part 2)
- OAA cant be exported so, converted to malate
- malate goes through to cytosol and is oxidatively decarboxylated back to OAA
- malate dehydrogenase and PEP carboxykinase
Decarboxylation of cytosolic OAA
- irreversible
- driven by GTP hydrolysis
- pairing carboxylation with decarboxylation makes GNG energetically possible
- PEPCK
- remove one C from OAA and add P
Dephosphorylation of fructose 1,6-bisphosphate
-hydrolysis reaction
-bypass the irreversible PFK-1 reaction
-important site for regulation
fructose 1,6-bisphosphatase
Regulation of Fructose 1,6-bisphosphatase
- high AMP levels inhibit
- allosterically inhibited by fructose 2,6-bisphosphate
- activator of PFK-1, made by PFK-2
- common regulator shows glycolysis and GNG are mutually exclusive
- Activated by high ATP
Dephosphorylation of glucose 6-P
- removal of P to free glucose and let it exit
- hydrolysis reaction
- bypass hexokinase irreversible reaction
- provides energetically favorable step to produce glucose
- GLUCOSE 6-PHOSPHATASE
- enzyme faces lumen so it can cleave glucose before it leaves
Von Gierke disease
-glucose 6-phosphatase deficiency
Energy summary of GNG
- endergonic pathway
- anabolic pathway
- for 1 glucose,
- 4 ATP and 2 GTP used
- 2 NADH are used
Regulation by glucagon
- inhibits PFK-2, lowers fructose 2,6-bisposphate
- inhibits pyruvate kinase so PEP is used for GNG and not glycolysis
- stimulates transcription of PEPCK to activate it
- inhibits glycolysis, activates GNG
Regulation by substrate availability
- protein breakdown in other tissues and AA release yields gluconeogenic precursors in the liver
- stimulates GNG
- ATP and NADH are provided by the oxidation of fatty acids in liver
Allosteric activation by acetyl CoA
- build up of acetyl CoA signials diversion of OAA for GNG
- activates pyruvate carboxylase
- inhibits PDH so pyruvate goes to GNG and not TCA
Allosteric inhibition by AMP
- fructose 1,6-bisphosphatase is inhibited by high AMP
- PFK-1 activated by High AMP
- assures two pathways are mutually exclussive
