Download Gluconeogenesis

Introduction
 Glucose remains the nearly universal and building
block in modern organisms, from microbes to
humans. In mammals, some tissues depend almost
completely on glucose for their metabolic energy.
 The human brain alone requires 120 g of glucose each
day, more than half of which is stored as glycogen in
muscle and liver.
 However, the supply of glucose from these stores is not
always sufficient . For these times, organisms need a
method of synthesizing glucose from non
carbohydrate precursors. This is accomplished by a
pathway called gluconeogenesis , which converts
pyruvate and related three and four carbon
compounds to glucose.
 Gluconeogenesis occurs in all plants, animals, fungi
and microorganisms. The import precursors of glucose
in animals are three-carbon compounds, which are
lactate, pyruvate, glycerol and certain amino acids.
 In mammals, gluconeogenesis takes place inside liver
and in minute quantities inside the renal cortex.
Is gluconeogenesis the reverse of
glycolysis?
 Both these pathways are not identical, running in opposite
reactions, although they share some common steps; 7 out
of 10 enzymatic reactions of gluconeogenesis are the
reverse of glycolytic reactions.
 However, three reactions of glycolysis are irreversible:
1. Conversion of glucose to glucose-6-phosphate by
hexokinase.
2. Phosphorylation of frusctose-6-phosphate to fructose1,6-bisphosphate by Phosphofructokinase-I.
3. Conversion of phosphoenolpyruvate to pyruvate by
pyruvate kinase.
 In gluconeogenesis, three
irreversible steps are
carried out by a separate
set of enzymes. Thus, both
glycolysis and
gluconeogenesis are
irreversible processes in
cells. In animals, both
pathways occur largely in
the cytosol, necessitating
their reciprocal and
coordinated regulation.
Conversion of Pyruvate to
Phosphoenolpyruvate
 This reaction cannot occur by the simple reversal of
the pyruvate kinase reaction of glycolysis .
 Pyruvate is first transported from the cytosol into the
mitochondria or is generated from alanine within
mitochondria by transamination. Then, pyruvate
carboxylase, a mitochondrial enzyme converts the
pyruvate to oxaloacetate.
Pyruvate+ HCO3- + ATP  oxaloacetate + ADP+ Pi
Conversion of Fructose-1,6bisphosphate to Fructose-6-phosphate
 The second glycolytic reaction that cannot participate
in gluconeogenesis is the phosphorylation of fructose6-phosphate by PFK-I .
 Because this reaction is highly exergonic and therefore
irreversible in intact cells, the generation of fructose6-phosphate from fructose-1,6-bisphosphate is
catalyzed by a different enzyme, Mg2+ dependent
fructose-1,6-bisphosphatase
Fructose-1,6-bisphosphate + H2O  fructose-6phosphate + Pi
Conversion of glucose-6-phosphate
to glucose.
 This is the final reaction of gluconeogenesis, the
dephosphorylation of glucose6-phosphate to yield
glucose .
 Reversal of the hexokinase reaction would require
phosphoryl group transfer from glucose-6-phosphate,
to ADP, forming ATP, an energetically unfavourable
reaction. Thus, the reaction is catalyzed by glucose6-phosphatase ; carries out simple hydrolysis.
Glucose-6-phosphate+ H2O glucose + Pi
Gluconeogenesis is Energetically
expensive, but essential.
 The net reaction for gluconeogenesis is
2 pyruvate+ 4ATP+ 2GTP+ 2NADH+ 2H+ +4H2O 
glucose +4ADP + 2GDP + 6Pi + 2NAD+
 Thus , it is an energetically expensive process . Much of
the high energy cost is necessary to ensure the
irreversibility of glycolysis.
 Hence , it is essential.
Glycolysis and Gluconeogenesis are
regulated reciprocally
 If both the processes were allowed to proceed
simultaneously, the result would be the consumption
of ATP and the production of heat . Hence, they are
regulated reciprocally.
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