Glyconeogenesis

Glyconeogenesis
Definition
• Term used to include all mechanisms and pathways
responsible for converting non- carbohydrates to glucose
and glycogen
• Production of glucose from other carbon skeletons is
necessary during fasting and starvation.
• The testes, erythrocytes, and kidney medullary cells are
exclusively dependent upon glucose oxidation for ATP
production.
Definition
• The brain requires adequate rates of gluconeogenesis
since it is the organ of highest daily glucose consumption.
• he brain can derive energy from ketone bodies
• The primary carbon skeletons used for gluconeogenesis
are derived from pyruvate, lactate, glycerol, and the
amino acids alanine and glutamine.
• The liver is the major site of gluconeogenesis.
• The kidney and the small intestine also have important
roles to play in this pathway.
Glyconeogenesis
• The major substrates are the glucogenic amino acids and
lactate, glycerol, and propionate.
• Liver and kidney are the major gluconeogenic tissues.
• Gluconeogenesis meets the needs of the body for
glucose when carbohydrate is not available in sufficient
amounts from the diet or from glycogen reserves.
• A supply of glucose is necessary especially for the
nervous system and erythrocytes
• Hypoglycemia causes brain dysfunction, which can lead
to coma and death.
• Glucose is also important in maintaining the level of
intermediates of the citric acid cycle even when fatty
acids are the main source of acetyl-CoA in the tissues.
• In addition, gluconeogenesis clears lactate produced by
muscle and erythrocytes and glycerol produced by
adipose tissue.
• Propionate, the principal glucogenic fatty acid produced
in the digestion of carbohydrates by ruminants, is a major
substrate for gluconeogenesis in these species.
GLUCONEOGENESIS INVOLVES GLYCOLYSIS, THE CITRIC
ACID CYCLE, & SOME SPECIAL REACTIONS
• Three non-equilibrium reactions catalyzed by
hexokinase, phosphofructokinase, and pyruvate
kinase prevent simple reversal of glycolysis for
glucose synthesis.
• They are circumvented as follows:
A. PYRUVATE & PHOSPHOENOLPYRUVATE
• Mitochondrial pyruvate carboxylase catalyzes the
carboxylation of pyruvate to oxaloacetate, an ATP-
requiring reaction in which the vitamin biotin is the
coenzyme.
• Biotin binds CO2 from bicarbonate as carboxybiotin prior
to the addition of the CO2 to pyruvate
• Biotin + ATP + HCO3– –> carboxy-biotin + ADP + Pi
Formation of Phosphoenolpyruvate
• The conversion of pyruvate to phosphoenolpyruvate
begins with the formation of oxaloacetate
• second enzyme, phosphoenolpyruvate carboxykinase,
catalyzes the decarboxylation and phosphorylation of
oxaloacetate to phosphoenolpyruvate using GTP (or ITP) as
the phosphate donor.
• Thus, reversal of the reaction catalyzed by pyruvate kinase
in glycolysis involves two endergonic reactions
B. FRUCTOSE 1,6-BISPHOSPHATE
& FRUCTOSE 6-PHOSPHATE
• The conversion of fructose 1,6-bisphosphate to fructose 6-
phosphate, to achieve a reversal of glycolysis, is catalyzed
by fructose-1,6-bisphosphatase.
• Its presence determines whether or not a tissue is capable
of synthesizing glycogen not only from pyruvate but also
from triosephosphates. It is present in liver, kidney, and
skeletal muscle but is probably absent from heart and
smooth muscle.
C. GLUCOSE 6-PHOSPHATE & GLUCOSE
• The conversion of glucose 6-phosphate to glucose is
catalyzed by glucose-6-phosphatase.
• It is present in liver and kidney but absent from muscle
and adipose tissue, which, therefore, cannot export
glucose into the bloodstream.
D. GLUCOSE 1-PHOSPHATE & GLYCOGEN
• The breakdown of glycogen to glucose 1-phosphate is
catalyzed by phosphorylase. Glycogen synthesis involves
a different pathway via uridine diphosphate glucose and
glycogen synthase.
• The relationships between gluconeogenesis and the
glycolytic pathway.
• After transamination or deamination, glucogenic amino
acids yield either pyruvate or Intermediates of the citric
acid cycle.
• Therefore, the reactions described above can account
for the conversion of both glucogenic amino acids and
lactate to glucose or glycogen.
• Propionate is a major source of glucose in ruminants and
enters gluconeogenesis via the citric acid cycle
SINCE GLYCOLYSIS & GLUCONEOGENESIS SHARE THE SAME
PATHWAY BUT IN OPPOSITE DIRECTIONS, THEY MUST BE
REGULATED RECIPROCALLY
• Changes in the availability of substrates are responsible for
most changes in metabolism either directly or indirectly
acting via changes in hormone secretion.
Three mechanisms are responsible for regulating the activity
of enzymes in carbohydrate metabolism:
(1) changes in the rate of enzyme synthesis,
(2) covalent modification by reversible phosphorylation, and
(3) allosteric effects.
Induction & Repression of Key Enzyme
Synthesis Requires Several Hours
• The changes in enzyme activity in the liver that occur

under various metabolic conditions .
• The enzymes involved catalyze nonequilibrium
(physiologically irreversible) reactions.
• The effects are generally reinforced because the activity of
the enzymes catalyzing the changes in the opposite
direction varies reciprocally.
Induction & Repression of Key Enzyme
Synthesis Requires Several Hours
• The enzymes involved in the utilization of glucose (ie,
those of glycolysis and lipogenesis) all become more active
when there is a superfluity of glucose, and under these
conditions the enzymes responsible for gluconeogenesis all
have low activity.
• The secretion of insulin, in response to increased blood
glucose, enhances the synthesis of the key enzymes.
Covalent Modification by Reversible
Phosphorylation Is Rapid
• Glucagon, and to a lesser extent epinephrine, hormones
that are responsive to decreases in blood glucose, inhibit
glycolysis and stimulate gluconeogenesis in the liver by
increasing the concentration of cAMP.
• In gluconeogenesis, pyruvate carboxylase, which catalyzes the
synthesis of oxaloacetate from pyruvate, requires acetyl-CoA as an
allosteric activator.
• The presence of acetyl-CoA results in a change in the tertiary
structure of the protein.
• This means that as acetyl-CoA is formed from pyruvate, it
automatically ensures the provision of oxaloacetate and,
therefore, its further oxidation in the citric acid cycle.
Importance of Gluconeogenesis
• A continual supply of glucose is necessary as a source of
energy, especially for the Nervous system and the
Erythrocytes.
• Gluconeogenesis mechanism is used to clear the
products of the metabolism of other tissues from the
blood, eg: Lactate, produced by Muscle and erythrocytes
and Glycerol, which is continuously produced by adipose
tissue.
Clinical Significance
• The enzyme Pyruvate carboxylase, deficiency is seen as an
inborn error of metabolism, where mental retardation is
manifested.
• Its incidence is one in 25,000 births.
• Pyruvate carboxylase gene is located in human chromosome
No. 11.
• In type II diabetes mellitus condition, there is a rise in the
blood glucose level.
• Gluconeogenesis is responsible for the production of
excessive Glucose after an overnight fast.

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What are the major sites of gluconeogenesis?

What are the major substrates used in gluconeogenesis?

• The changes in enzyme activity in the liver that occur

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