GLUCONEOGENESIS

Definition - Synthesis of glucose from non

carbohydrate precursors such as pyruvate, lactate,
glucogenic amino acids, propionate and glycerol.

Average adult human uses 120 g/day of glucose,

mostly in the brain (75%)
Site liver (90%)
- cortex of the kidney (10%)
- both cytosol and mitochondria
 Metabolites feed into
gluconeogenesis at various points
All amino acids can
feed into
Gluconeogenesis
except leucine &
lysine
 Gluconeogenesis is the modifications and adaptation
of glycolytic pathway and citric acid cycle pathway.

By pass enzymes
1.Phosphoenol pyruvate carboxykinase
(PEPCK) between pyruvate and PEP.
2.Fructose 1,6-bisphosphatase
between F 1,6-bisphosphate and F6P.
3. Glucose 6 phosphatase
between glucose 6 P and glucose.

Key enzymes
1.Phosphoenol pyruvate carboxy kinase
2.Fructose 1,6-bisphosphatase.
3.Glucose 6 phosphatase.
4.Pyruvate carboxylase.
Irreversible glycolytic steps bypassed
Glycolysis Gluconeogenesis

1. Hexokinase (HK) by Glucose-6-phosphatase

2. Phosphofructokinase-1 by Fructose 1,6-

(PFK-1) bisphosphatase (FBP-1)

3. Pyruvate kinase (PK) by Pyruvate carboxylase &

Phosphoenolpyruvate
carboxykinase (PEPCK)

These 3 key enzymes

First bypass step is
generation of PEP
from pyruvate via
oxaloacetate

Note:
In order to cross the
mito membrane,
oxaloacetate must:
1. be reduced to
malate
2. go through the
malate shuttle
3. be reoxidized to
oxaloacetate
 OAA produced in Malate Shuttle
mitochondria by pyruvate
carboxylase

mitochondrial membrane
is impermeable to OAA

OAA reduced to malate

in matrix

malate transporter in mito.

membrane transports
malate to cytosol

cytoplasmic malate
dehydrogenase reoxidizes
malate to OAA
 First bypass reaction
Glycolysis Gluconeogenesis
Second & Third bypass reactions
 Precursor for gluconeogenesis
Glycerol to Glucose

Lipolysis
 Glycerol is released during the hydrolysis of
triacylglycerols in adipose tissue (Lipolysis) and is
delivered by the blood to the liver.

Glycerol glycerol kinase glycerol phosphate

ATP ADP Isomerase

DHAP Glucose
Adipocytes cannot phosphorylate glycerol because they
essentially lack glycerol kinase
 Lactate to Glucose (Cori Cycle)
Lactate is released into the blood from red
blood cells (no mitochondria) & exercising
muscle cells. It is taken up by liver & converted
to glucose released back into circulation
 Cori cycle
High NADH/NAD+ Low NADH/NAD+
 Glucose Alanine cycle

Amino acids derived from hydrolysis of tissue proteins are the major
source during fasting
 Glucose Alanine cycle
Pyruvate is the end product of glycolysis & it
undergoes transamination reaction produce alanine.

Pyruvate - ketoglutarate

PLP ALT
Alanine Glutamate

Alanine formed in the muscle is transported to liver

and converted to glucose & released into the
circulation & then to muscle.
 Regulation of gluconeogenesis
Pyruvate kinase regulation (Active form- Dephosphorylated)

Alanine,

AMP, FBP2
Effects of Fructose-2,6-Bisphosphate
Fructose-2,6-bisphosphate allosterically activates
glycolysis enzyme Phosphofructokinase-1
Fructose-2,6-bisphosphate inhibits gluconeogenesis
enzyme Fructose-1,6-bisphosphatase
 Fructose-2,6-bisphosphate is synthesized and degraded
by a bi-functional enzyme that includes two catalytic
domains

PFK-2 and FBPase-2

Active form of PFK2 ------------- Dephosphorylated
Active form of FBPase 2 ------- Phosphorylated

Inactive form of PFK2 ----------- Phosphorylated

Inactive form of FBPase 2 -------Dephosphorylated
Bifunctional enzyme

Activates PFK1
Inhibits F-1,6-
bisphosphatase

Inhibits PFK1
Activates F-1,6-
bisphosphatase
 Induction & Repression of enzyme
synthesis
Glucocorticoids,
Glucagon, Insulin
Epinephrine
+ -

Pyruvate carboxylase,PEPCK,
F1,6 BPtase, G 6 phosphatase
 Learning outcome of
Gluconeogenesis
Describe the gluconeogenic pathway from various
sources including glycerol.
Describe the importance of liver in gluconeogenesis
Describe the Cori Cycle and glucose- alanine cycle
and their importance.