Gluconeogenesis

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Gluconeogenesis
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Learning Objectives
Define gluconeogenesis. Identify the tissues or
cell types where gluconeogenesis occurs. Identify
the tissues or cell types where gluconeogenesis
does not occur. Identify the reason why
gluconeogenesis does not occur in these
tissues. Identify the important glucogenic
precursors of glucose in animals.
Identify the primary function of gluconeogenesis
in vertebrates (and humans).
Identify the three irreversible reactions of
glycolysis that must be bypassed in
gluconeogenesis.
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Definition
Gluconeogenesis the biosynthesis of a
carbohydrate (glucose) from simpler,
non-carbohydrate precursors such as pyruvate. The
formation of glucose from non-hexose precursors.
In higher animals, gluconeogenesis occurs
primarily in the liver, and to a much smaller
extent in the renal cortex (kidney).
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Glucose
The important non-hexose precursors of glucose in
animals are lactate, pyruvate, glycerol, and
certain amino acids.
Glucose-6-phosphate
Glycerol
Phosphoenolpyruvate
Triacylglycerol
TCA Cycle
Pyruvate
Glucogenic amino acids
Lactate
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The glycolytic conversion of glucose to pyruvate
is a central pathway in carbohydrate
catabolism. The conversion of pyruvate to glucose
is a central pathway in gluconeogenesis.
Both of these pathways occur in the cytosol. They
are not identical, but seven of the ten enzymatic
reactions of gluconeogenesis are the reverse of
glycolytic reactions. Three reactions of
glycolysis are essentially irreversible and must
be bypassed by a separate set of enzymes.
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The three irreversible reactions of glycolysis
(1) hexokinase glucose to glucose-6-phosphate
(2) phosphofructokinase-1 fructose-6-phosphate
to fructose-1,6-bisphosphate
(3) pyruvate kinase phosphoenolpyruvate to
pyruvate
These irreversible glycolytic reactions must be
bypassed in gluconeogenesis (pyruvate to glucose).
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The conversion of pyruvate to phosphoenolpyruvate
Lactate
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Phosphoenolpyruvate (PEP)
This route from pyruvate to PEP is utilized when
cytosolic lactate levels are low.
Pyruvate is first transported into the
mitochondria or generated from alanine within the
mitochondria by transamination.
Pyruvate
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Pyruvate carboxylase is a mitochondrial enzyme
that requires biotin as a coenzyme. It is the
first regulatory enzyme in gluconeogenesis and is
positively affected by acetyl CoA. The reaction
is also anaplerotic, replenishing intermediates
in the TCA cycle.
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low NADH
Cytosolic NADH is consumed in gluconeogenesis
(the reversible conversion of 1,3-bisphosphoglycer
ate to glyceraldehyde-3-phosphate from
glycolysis). It cannot proceed without NADH.
Cytosol
cytosolic malate dehydrogenase
This set of reactions effectively moves reducing
equivalents (NADH) from the mitochondria to the
cytosol where they are scarce.
mitochondrial malate dehydrogenase
high NADH
Mitochondria
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PEP carboxykinase
This reaction requires Mg2 and utilizes GTP as
the phosphate donor. This reaction is
essentially reversible with the formation of one
high energy compound (PEP) at the expense of
another (GTP).
The CO2 lost here is the same CO2 added in the
pyruvate carboxylase reaction.
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This second (and shorter) pyruvate to PEP bypass
predominates when lactate is the gluconeogenic
precursor.
PEP
This pathway makes use of lactate produced by
glycolysis in erythrocytes or anaerobic muscle
Mitochondria
The conversion of lactate to pyruvate in the
hepatocyte cytosol yields NADH, and the export of
reducing equivalents from the mitochondria is
unnecessary.
Cytosol
Lactate
Pyruvate
lactate dehydrogenase (LDH)
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The second bypass reaction
fructose-1,6-bisphosphate H2O
fructose-6-phosphate Pi
fructose-1,6-bisphosphatase
This is an essentially irreversible hydrolysis of
fructose-1,6-bisphosphatase yielding inorganic
phosphate (not phosphoryl group transfer to ADP).
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The third bypass reaction a simple hydrolysis
of a phosphate ester
glucose Pi
Glucose-6-phosphate H2O
glucose-6-phosphatase
Glucose-6-phosphatase is a Mg2 activated enzyme
and is found on the lumenal side of the
endoplasmic reticulum of hepatocytes and renal
cells. This enzyme is not present in muscle or
in the brain, and gluconeogenesis does not occur
in these tissues.
In muscle and brain tissue, gluconeogenesis (the
formation of glucose from non-hexose precursors)
may not occur, but glucose-6-phosphate can still
be produced from non-hexose precursors.