Biochemistry II Lecture 4
Topic: 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.
The brain requires adequate rates of gluconeogenesis since it is the organ of highest daily
glucose consumption.
The 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.
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Biochemistry II Lecture 4
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 CO 2 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
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Biochemistry II Lecture 4
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
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Biochemistry II Lecture 4
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.
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.
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Biochemistry II Lecture 4
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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