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Class 10. Gluconeogenesis (4 Unique Reactions (Pyruvate -> Oxaloacetate…
Class 10. Gluconeogenesis
Summary and comparison with Glycolysis
Overall reaction
Six ATP equivalents used
4 ATP
2 GTP
2 pyruvate converted to glucose
Compare with energy chart of 11 reactions (Fig 18.22)
reciprocal control between glycolysis and gluconeogenesis
Depends on glucose availability as well as energy status
Energy status: AMP/ATP
low energy
glycolysis UP
provide ATP
high energy
gluconeogenesis UP
use energy to produce glucose and glycogen
Substrate-level control
Glucose-6-Phosphatase
Allosteric control
Acetyl-CoA
Citrate
F-2,6-P2
ATP/AMP
Whole body Physiology in humans
Cori cycle
Lactate -> pyruvate -> glucose
Redistribution of lactate and glucose
Lactate buildup in muscle
Shortage of oxygen
NAD+ cannot be regenerated through cellular respiration
NADH -> NAD+ by reducing pyruvate to lactate
Lactate transported to liver
Lactate reoxidized to pyruvate
pyruvate can be converted to glucose
Liver shares metabolic burden of exercise
Basics
Example of anabolic pathway
Comparison with a parallel catabolic pathway (glycolysis)
appears to be reverse of glycolysis
Commonality
7 reactions of glycolysis
Difference
3 reactions of glycolysis that are highly exergonic
4 reactions of gluconeogenesis
Pyruvate -> Oxaloacetate
Oxaloacetate -> PEP
Fructose 1,6-P2 -> Fructose 6-P
Glucose 6-P -> Glucose
Reason for difference
Gluconeogenesis is endergonic
Different enzymes are required for separate regulation of the two pathways
Physiological role
Backup supply of glucose
compare with fat: catabolism does not generate glucose
Possible precursors of gluconeogenesis:
enter at Pyruvate, Oxaloacetate, or DHAP
lactate, amino acids, glycerol, and TCA cycle intermediates
4 Unique Reactions
Pyruvate -> Oxaloacetate
Substrates and Products
Pyruvate + Bicarbonate + ATP -> Oxaloacetate + ADP + Pi
Direction: Driven forward with ATP energy
Enzyme: Pyruvate Carboxylase
Mechanism
Biotin as carboxyl group carrier
Biotin linked to a lysine residue
ATP activates bicarbonate
Bicarbonate transferred to Biotin
Regulation
Allosteric Activator
Acetyl-CoA and ATP
Location
Mitochondrion
Compartmentalization helps preventing futile cycle of simultaneous glycolysis and gluconeogenesis
Transport of Oxaloacetate from Mitochondria to Cytoplasm
Conversion to malate and back to Oxaloacetate
Oxaloacetate -> Malate: reverse of TCA cycle reaction through malate dehydrogenase
Coupled with NAD+->NADH
Oxaloacetate -> PEP
Substrates and Products
Oxaloacetate + GTP -> PEP + GDP + CO2
Direction: driven forward to PEP production
Energetically favorable
GTP energy used
Equivalent of using ATP because ATP is used to regenerate GTP from GDP
Enzyme: PEP carboxykinase (PEPCK)
Fructose 1,6-P2 -> Fructose 6-P
Substrates and Products
Fructose 1,6-P2 + H2O -> Fructose 6-P + Pi
Direction: driven forward
hydrolysis of phosphate ester is thermodynamically favorable
Enzyme: Fructose 1,6-bisphosphatase - regulation
activation
citrate
inhibition
fructose 2,6-bisphosphate
generated by PFK-2 enzyme
Different from PFK (or PFK-1)
reversed to F-6-P by Fructose-2,6-bisphosphatase (F-2,6-BPase)
PFK-2 vs F-2,6-BPase
Two enzyme activities are in the same protein!
"Bifunctional" or "Tandem" enzyme
Allosteric regulation: F-6-P
PFK-2 activated
F-2,6-BPase inhibited
Regulation by phosphorylation: cAMP-dependent protein kinase
PFK-2 inhibited
F-2,6-BPase activated
use ATP
cAMP-dependent protein kinase activated by glucagon
AMP
synergistic
Opposite to PFK regulation
Glucose 6-P -> Glucose
Substrates and Products
Glucose 6-P -> Glucose + Pi
Direction: driven forward
exergonic due to phosphate ester hydrolysis
Enzyme: glucose 6-phosphatase
Body Location:
absent from muscle and brain - No glucose produced through gluconeogenesis
present in liver and kidney
Cellular location: Endoplasmic Reticulum
Transporters: T1, T2, T3
T1: G-6-P from cytosol to ER
T2: Glucose from ER to cytosol
T3: Pi from ER to cytosol
GLUT2: Glucose from cytosol to extracelluar space