GLUCONEOGENESIS

Synthesis of glucose from noncarbohydrate sources.
Major precursors are lactate and alanine in the liver and kidney.
lactate - active skeletal muscles
glycerol - lipid catabolism
amino acids - diet and protein catabolism
Used to maintain blood glucose levels when glycogen supplies are low or depleted.
Major site of occurrence is the liver, but also occurs in kidney.
Designed to make sure blood glucose levels are high enough to meet the demands of brain
and muscle (cannot do gluconeogenesis).
NOT the reverse of glycolysis. Why?
PFK, PK, and hexokinase catalyze metabolically irreversible steps.
Solution: by-pass these steps, but use all the other enzymes.
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1) pyruvate ---> phosphoenolpyruvate
ATP ADP + Pi GTP GDP
pyruvate ------------------> oxaloacetate -----------------> PEP
HCO3
- pyruvate PEP carboxykinase
carboxylase
TCA
Cycle
Pi
2) fructose 1,6 bisphosphate fructose 6-phosphate
fructose 1,5-bisphosphatase
glucose 6-phosphatase
3) glucose 6-phosphate --------------------------> glucose
This enzyme is bound to ER membrane, but faces ER lumen.
GLUT7 transporter must transport glucose 6-phosphate into ER lumen.
Enzyme not found in membrane of brain or muscle ER.
Consequences?
PRECURSORS FOR GLUCONEOGENESIS
1) lactate
Cori cycle - no net gain or loss of glucose
Anaerobic respiration of pyruvate.
2) amino acids
glutamate -ketoglutarate
pyruvate -----------------------------------> alanine
transamination
3) glycerol
glycerol kinase
glycerol ------------------> glycerol 3-phosphate -----> DHAP
If glycerol 3-phosphate dehydrogenase is embedded in inner mitochondrial
membrane, e- passed to ubiquinone.
If enzyme is cytosolic, NADH is also a product.
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REGULATION OF GLUCONEOGENSIS
Glycolysis and gluconeogenesis are reciprocally regulated.
If both pathways were activated, e.g.
fructose 6-phosphate + ATP ------> fructose 1,6-bisphosphate + ADP
fructose 1,6-bisphosphate + H2O ---> fructose 6-phosphate + Pi
net reaction: ATP + H2O ---> ADP + Pi
Called substrate cycle ---> “burn” 4 ATPs for every 2 ATPs made (can be used to
generate heat).
Reason why enzymes are regulated --> prevents this from happening.
Two regulatory points are the two steps which had different enzymes.
fructose 1,6-bisphosphatase
inhibited by AMP and fructose 2,6-bisphosphate
pyruvate carboxylase
activated by acetyl CoA
PENTOSE PHOSPHATE PATHWAY
Provides NADPH (serves as e- donor) and forms ribose 5-phosphate (nucleotide
synthesis).
Pathway active is tissues that synthesize fatty acids or sterols because large
amounts of NADPH needed.
In muscle and brain, little PPP activity.
All reactions are cytosolic.
Divided into 2 stages:
1) oxidative
glucose 6-phosphate +2 NADP+ + H2O --> ribulose 5-phosphate +
2 NADPH + CO2 + 2H+
2) nonoxidative
Uses transketolases (transfers 2-C units) and transaldolases
(transfers 3-C units).
Links PPP with glycolysis.
Used to catalyze these types of reactions:
C5 + C5 <----> C7 + C3
C7 + C3 <----> C4 + C6
C5 + C4 <----> C3 + C6
All reactions are reversible --> very flexible pathway.
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Example:
If ribose 5-phosphate needed, fructose 6-phosphate + glyceraldehyde 3-phosphate taken
from glycolysis and channeled through PPP to make product.
If NADPH is needed, then ribulose 5-phosphate is converted to glyceraldehyde 3-phosphate
and fructose 6-phosphate --> converted to glucose 6-phosphate --> more NADPH made.
If use PPP, 1 glucose can be completely oxidized to 12 NADPH and 6 CO2.
If NADPH and ATP are needed, ribulose 5-phosphate converted into glyceraldehyde 3-
phosphate and fructose 6-phosphate --> glycolysis --> pyruvate.