Biochemistry
Lecture 11
Gluconeogenesis
Gluconeogenesis
-Metabolic Pathways are Irreversible
∆G between the 1st & last metabolite is large & neg.
- If 2 metabolites are interconvertible (metab 1
metab 2),
the path from Metab 1  Metab 2 must be different from that
of Metab 2  Metab 1
A
B
Metab1
Metab2
Y
X
A. Circumventing Pyruvate Kinase - Conversion of Pyruvate
to Phosphoenolpyruvate
1. Carboxylation of pyruvate to oxaloacetate √
2. Transport of oxaloacetate out of mitochondria
Oxaloacetate
NADH + H+
NAD+
Malate
cyto
mito
Oxaloacetate
NADH + H+
NAD+
Malate
Inner mito. Memb.
3. PEP Carboxykinase: decarboxylates and adds
phosphate
B. Circumventing PFK – dephosphorylation of F1,6BP
• Dephosphorylation is not phosphorylation in reverse!
• Reverse Phosphorylation of ADP by F1,6 BP to generate F6P (and
ATP) would be steeply uphill:
F1,6 BP + ADP
F6P + ATP
∆G° = +3.4 kcal/mol
• Instead, dephosphorylation is carried out:
F1,6 BP + H2O
F6P + PO4
∆G° = -3.9 kcal/mol
• Reverse Phosphorylation would be mediated by PFK
• Dephosphorylation is mediated by F1,6BPase
C. Circumventing Hexokinase – dephosphorylation
of G6P
• Mediated by G6Pase
• G6Pase is present only in liver and kidney
• Hence, these are the only tissues that can
synthesize and secrete glucose into the blood
The Gluconeogenic Response is Activated
Largely by the State of Feeding/Fasting
Glycogen
Blood Glucose
Blood Glucose
Glucose
Blood Glucose
Pyruvate
Alanine
Acetyl CoA
FA’s
The Cory
Cycle
Gluconeogenesis & Glycolysis can Occur at the
Same Time in Different Organs
IN MUSCLE
IN LIVER
Glucose
Gluconeogen.
Pyruvate
B
L
O
O
D
Glucose
Glycolysis
Pyruvate
Alanine
Alanine
Lactate
Lactate
RED BLOOD CELLS
Glucose
*** The main substrate
here is LACTATE***
Pyruvate
Lactate
Regulation of Metabolism
Overview of Energy Metabolism
FATS
POLYSACCHARIDES PROTEINS
Stage I
Digestion
Fatty Acids,
Glucose and
Glycerol
other sugars
Amino Acids
Stage II
Anaerobic
Acetyl CoA
ATP ADP
O2
eOxidative
Phosphorylation
TCA
cycle
CoA
CO2
Stage III
Aerobic
Principles of Regulation
• The flow of metabolites through the pathways is
regulated to maintain homeostasis
• Sometimes, the levels of required metabolites must be
altered very rapidly
– Need to increase the capacity of glycolysis during the action
– Need to reduce the capacity of glycolysis after the action
– Need to increases the capacity of gluconeogenesis after
successful action
Rates of a Biochemical Reaction
• Rates of a biochemical reaction depend on many
factors
• Concentration of reactants
• Activity of the catalyst
– Concentration of the enzyme
– Intrinsic activity of the enzyme
• Concentrations of effectors
– Allosteric regulators
– Competing substrates
– pH, ionic environment
• Temperature
Reactions Far From Equilibrium
are Common Points of Regulation
Hexokinase
• Isozymes are different
enzymes that catalyze
the same reaction
• They typically share
similar sequences
• Their regulation is
often different
eg. G6P is structurally similar to glucose, and competes with glucose for active
site of hexokinase
P
PFK
Allosteric site
Active site
Fructose-2,6-bisphosphate
Two Alternative Fates for
Pyruvate
• Pyruvate can be a source of new glucose
– Store energy as glycogen
– Generate NADPH via pentose phosphate pathway
• Pyruvate can be a source of acetyl-CoA
– Store energy as body fat
– Make ATP via citric acid cycle
• Acetyl-CoA stimulates glucose synthesis by activating
pyruvate carboxylase
Pancreas
Adrenal Medulla
+
Glucagon
Liver
Epinephrine
Brain
Muscle
Glycogen
Glycogen
+
+
+
+
Glucose
(Blood)
Glucose
F6P
+
PFK
F1,6BP
PK
Pyruvate
F2,6BP
Glucose
+
F6P
+ PFK
F1,6BP
PK
Pyruvate
F2,6BP