DR. AWS HASSAN
4
TH
LECTURE
( Gluconeogenesis )
[ Synthesis of glucose from non- carbohydrate compounds ]
● The major precursors (substrates ) for gluconeogenesis are :
1 - Lactate
2 - Glycerol
3 - Glucogenic amino acids ( main substrate )
4 - Odd-chain fatty acid (Propionate) .
● Gluconeogenesis occurs mainly in the liver and to less extent in the kidney ; it is
partly cytosolic and partly mitochondrial .
● depending on the precursor , gluconeogenesis involves reactions of glycolysis , citric
acid cycle , and some special reactions .
Lactate :
● Lactate accumulation associated with intense muscular exercise causes muscle cramps
( fatigues ) since lactate is acidic and cause decrease in pH affecting and inhibiting the
activity of the enzyme PFK-1 of glycolysis .
● cardiac muscle can metabolize and clear off lactate from the blood since the enzyme
LDH in cardiac muscle (LDH
1
) has high affinity for lactate and preferentially convert
lactate to pyruvate which is then oxidized through citric acid cycle .
Gluconeogenesis from Lactate :
Pyruvate obtained from lactate is converted to glucose using the reversible reactions
of glycolysis and the irreversible reactions are bypassed
in reverse by different
enzymatic reactions ( special reactions called bypass reactions ) .
Gluconeogenesis from amino acids :
● Quantitatively, the amino acid alanine is the major glucogenic amino acid .
● During fasting , starvation and in diabetes mellitus , amino acids from muscle
proteins are released .
■ Most amino acids are partially oxidized in the muscle by citric acid cycle generating
ATP and the remaining carbons are converted to Alanine & Glutamine and released
into blood :
■ Alanine is formed in the muscle by transamination of different amino acids
with
Pyruvate produced either by glycolysis of muscle glycogen or from Malate
by
Malic enzyme .
α–amino acid + Pyruvate ←─────→ α– ketoacid + Alanine
■ Glutamine is formed from α-ketoglutarate point . Glutamine may also be
converted to alanine by tissues such as gut & kidney and released into blood .
● Alanine released into the blood by muscles is transported to liver where it is
transaminated with α-ketoglutarate to
Pyruvate & Glutamate
.
GPT
alanine + α-ketoglutarate ←─────→ Pyruvate + Glutamate
■ Pyruvate is then converted to Glucose through gluconeogenesis pathway .
■ Glutamate formed in the liver is oxidatively deaminated by the enzyme glutamate
dehydrogenase , and the ammonia released is converted to urea .
N O T E S
:
■ Gluconeogenesis is energy expensive pathway ; energy required for gluconeogenesis
is obtained from oxidation of even-chain fatty acids .
■ Liver is qualified as the main site for gluconeogenesis for the following
biochemical characteristics :
a - Liver lactate dehydrogenase ( LDH
1
) has high affinity for lactate .
b - The enzyme glucose-6-phosphatase is significantly active only in liver ; it is
absent from muscle .
c - the enzyme glycerol kinase is present in significant amounts in liver , kidney
and intestine .
d - Glutamate dehydrogenase is present mainly in liver mitochondria .
e - Transaminase activities are high in liver specifically GPT .
■
Significance of gluconeogenesis :
The important metabolic roles and significances of gluconeogenesis are :
1.
To maintain the supply of glucose for the brain and erythrocytes during fasting
and starvation when sufficient carbohydrate is not available from diet and
glycogen stores to meet the needs of the body .
2. Gluconeogenesis clears acidic lactate produced by muscle & erythrocytes and
clears glycerol produced from the hydrolysis of triglycerides in adipose tissue .
