Gluconeogenesis 160107095046

GLUCONEOGENESIS
• The synthesis of glucose from non-carbohydrate sources

• Site:
• Mostly takes place in liver (Approx.

1 kg glucose/day) & Kidney
• Occurs mainly in cytosol – some precursors are

produced in mitochondria
• Notable precursors are
 Pyruvate
 Glycerol  Propionate
 Lactate  Glucogenic Amino acids
Glycolysis Net Reaction:
Glucose + 2 ADP + 2 NAD+ + 2 Pi  2 Pyruvate + 2 ATP

+ 2 NADH + 2 H+ + 2 H2O
Gluconeogenesis Net Reaction:
2 Pyruvate + 4 ATP + 2 GTP + 2 NADH + 2 H+ + 6 H2O

 Glucose + 4 ADP + 2 GDP+ 2 NAD+ + 6 Pi
Why do we synthesize glucose?
 Need to maintain glucose levels within a narrow
range in blood.
 Brain, erythrocytes, testes & kidney medulla are
dependent on glucose for continuous supply of energy
 Skeletal muscles in exertion (anaerobic conditions)
use glucose at a rapid rate
 In fasting to meet the basal requirements of the body
for glucose –essential for the survival
 Effectively prevent the accumulation of certain
metabolites in blood. E.g. lactate, glycerol, propionate
etc.
PATHWA
Y #1
Gluconeogenesis:
 glycolysis going backwards #3

 3 places differ- control points in
glycolysis
 4 new enzymes (eukaryotes)
 Energy consumed
#10
1, 3
Gluconeogenesis:
 Total 6 ATP needed
 4 needed to
overcome barrier of
production of 2
mol of PEP
The Irreversible Steps
1) Pyruvate  PEP; reversing the pyruvate kinase step of glycolysis
Malate Shuttle
Gluconeogenesis:
 Irreversible steps II & III

2) Fru-1,6-biP  Fru-6-P; reversing the PFK-1 step of glycolysis
 Absent in smooth muscle and heart muscle

3) Glucose-6-P  Glucose; Glucose 6 phosphatase
 Mostly present in liver and kidney

 Absent in muscle and brain
Overlook
PFK 1
What is the major
precursor?
• The major precursor for glucose biosynthesis is
pyruvate
What are the sources of
pyruvate?
1. LACTATE
• Mostly from muscle.

• Lactate is produced in great quantities during
exertion.
• Lactate is released from the muscles to the blood
and travels to the liver for conversion to pyruvate
and, ultimately to glucose - Cori cycle.
Cori
Cycle
Glucose • In Muscle
Lactate
• In Liver
Glucose
Significance:
• The lactate produced in the muscle is efficiently utilized
• It counteracts lactic acidosis
2. GLUCOGENIC AMINO
ACIDS
• Glucose is not readily available in D.M & starvation
• Carbon skeleton of Glucogenic amino acids results

in the formation of pyruvate or the intermediates of
TCA cycle
• It results in the formation of glucose

Glucose –Alanine Cycle
(Cahill cycle)
• Alanine is transported to liver, transaminated
to
pyruvate & converted to glucose glycolyti
pathwa pyruvate c transaminated
y to
alanine
• Significa
blood sugar level using amino
nce:acids(alanine) in special situations
• Incre
• Muscle wastage in uncontrolled D.M explained
ase
by this factor
 The liver can also use the amino acid
Alanine like Lactate
 Following transamination to pyruvate,

gluconeogenesis allows the liver to
convert it to glucose for secretion into
the blood
3.
GLYCEROL
• DHAP can be converted to glyceraldehyde-3-P by
triose phosphate isomerase
Glyceraldehyde -3-P
fructose -1,6-bisphosphate
glucose
Glycerol to Glucose
Adipose tissue
Lipolysis by hormone dependent LPL
Glycerol
Glycerol kinase
Glycerol – 3 phosphate
Glyceraldehyde 3 P dehydrogenase
Dihydroxy acetone-P
Triose isomerase
Glyceraldehyde-3-P
Reversal of glycolysis
Gluconeogenesis
4. PROPIONYL
CoA
• Propionyl CoA enters the pathway via TCA cycle
after conversion to Succinyl CoA
• In humans propionic acid is not synthesized

but it is formed as a metabolic intermediate.
• Eg: formed from oxidation of odd-chain fatty

acids
Regulation
• RATE LIMITING ENZYMES:
Glucose 6 phosphatase
Fructose 1, 6 bisphosphatase
Pyruvate carboxylase
Glucose 6 phosphatase
• Allosteric regulation(metabolites):
glucose (-)
glucose 6 phosphate, acetyl
CoA (+)
• Covalent modification(Hormones):
insulin (-)
glucagon (+)
Fructose 1, 6 bisphosphatase
• Allosteric regulation(metabolites):
ATP, acetyl coA(citrate) (+)

AMP, ADP, fructose 2,6 bisphosphate(-)
• Covalent modification(Hormones):
insulin (-)
glucagon (+)
Pyruvate carboxylase
Allosteric regulation(metabolites):
Acetyl CoA (citrate) (+)

AMP, ADP (-)
Covalent modification(Hormones):
insulin (-)
glucagon, epinephrine (+)
Pyruvate can
go “up” or
“down”
depending
upon energy
needs
Reciprocal
Regulation of
glycolysis and
gluconeogenesis

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GLUCONEOGENESIS

• The synthesis of glucose from non-carbohydrate sources

• Mostly takes place in liver (Approx.

• Occurs mainly in cytosol – some precursors are

Glucose + 2 ADP + 2 NAD+ + 2 Pi  2 Pyruvate + 2 ATP

Gluconeogenesis Net Reaction:

2 Pyruvate + 4 ATP + 2 GTP + 2 NADH + 2 H+ + 6 H2O

 glycolysis going backwards #3

 Irreversible steps II & III

 Absent in smooth muscle and heart muscle

 Mostly present in liver and kidney

• Mostly from muscle.

• Carbon skeleton of Glucogenic amino acids results

• It results in the formation of glucose

 Following transamination to pyruvate,

Lipolysis by hormone dependent LPL

• In humans propionic acid is not synthesized

• Eg: formed from oxidation of odd-chain fatty

• RATE LIMITING ENZYMES:

ATP, acetyl coA(citrate) (+)

Acetyl CoA (citrate) (+)

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