Gluconeogenesis

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Ferchmin 2009/gluconeogenesis
GLUCONEOGENESIS
Summary of handout Comparison with glycolysis,
unique and shared enzymes Role of biotin in
gluconeogenesis (and comparison with vitamin K
which is not involved in gluconeogenesis) "Revers
al" of pyruvate kinase. Participation of the
mitochondria "Reversal" of Phosphofructokinase "
Reversal" of hexokinase The Cori and alanine
cycles Regulation. Role of insulin and glucagon
in glycolysis and gluconeogenesis. Glycogenic and
ketogenic compounds Metabolic role of
gluconeogenesis
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COMPARISON BETWEEN GLYCOLYSIS AND GLUCONEOGENESIS
The overall reaction of gluconeogenesis is
COOH 2 CO 4 ATP 2 GTP 2 NADH 2H
2 H2O ? glucose 4 ADP 2 GDP 6 Pi 2 NAD
CH3 ?G' -9 Kcal/mole
The overall reaction of glycolysis is
COOH
Glucose 2
ADP 2 Pi 2 NAD ? 2 CO 2 ATP 2 NADH
2H 2 H2O

CH3
?G' -20 Kcal/mole
Glycolysis yield 2 ATP/glucose plus a net
dissipated - 9 Kcal/mole. Gluconeogenesis is
really bad news, it consumes the equivalent of 6
ATP/glucose synthesized. Why would be a need for
such a metabolic pathway?
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Gluconeogenesis is the synthesis of glucose from
precursors that are not sugars, like lactate,
pyruvate, glycerol or glycogenic amino acids. The
synthesis of glucose from other sugars simply is
not gluconeogenesis. The neo means de novo from
non-carbohydrate molecules. There is no
gluconeogenesis from fatty acids except the rare
ones with odd number of carbons that have a
minute contribution to the synthesis of glucose
of rather academic value just to stimulate your
intellect! Fatty acids contribute to the fasting
organism with ATP through ß-oxidation and
oxidation of ketone bodies in the Krebs cycle.
Ketone bodies only partially substitute for
glucose and are synthesized by a pathway
different from gluconeogenesis. Ketone bodies are
potentially dangerous in the absence of glucose
(you will study this later). In conclusion
lipids can spare glucose because they provide for
ATP that otherwise would be synthesized in
glycolysis. But lipids do not substitute glucose.
We need about l60 grams of glucose per day, 120
grams are needed for the brain and 40 grams for
muscle, erythrocytes, eye lens cells, kidneys
medulla, etc. Approximately 200 grams are stored
in hepatic glycogen. Gluconeogenesis provides the
necessary glucose during fast. The complete
gluconeogenesis occurs in liver and a small
fraction in kidney. Since glycolysis is
irreversible gluconeogenesis cannot be the
reversal of glycolysis. The enzymes that catalyze
the irreversible reactions in glycolysis are
overridden in various ingenious ways in
gluconeogenesis.
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We will study gluconeogenesis by comparing it
with glycolysis
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The last glycolytic step catalyzed by pyruvate
kinase is irreversible, the free energy change is
high, -7.5 Kcal/mole. To reverse this step in
gluconeogenesis two enzymes are used and the
process takes place in two cellular compartments.
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Enzymatic differences between glycolysis and
gluconeogenesisa) Regulatory enzymes ____________
__________________________________________________
____Glycolysis Gluconeogenesis ______________
__________________________________________________
__ Hexokinase Glucose 6-phosphatase Phosphof
ructokinase Fructose 1,6-bisphosphatase
Pyruvate
Pyruvate kinase carboxylase Phosphoenol
pyruvate carboxykinase ____________________
______________________________________________b)
The remaining enzymes are shared by both
pathways _________________________________________
_________________________Essential concept
Pathways for breakdown and synthesis of a
particular metabolite are always different,
utilizing unique enzymes in one or more steps.
The difference usually is in the regulatory
enzymes.
Pyruvate carboxylase is mitochondrial and hepatic
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With reference to pyruvate carboxylase This part
is a pop up about a different subject
marginally related to gluconeogenesis but of
practical importance (NBE). There are two
vitamins involved in CO2 incorporation in
mammalian tissues biotin and vitamin K. In
gluconeogenesis biotin is a cofactor for pyruvate
carboxylase. Biotin binds avidly to AVIDIN.
Vitamin K is involved in the posttranslational
synthesis of ?-carboxyglutamate involved
prominently in blood coagulation. Biotin is
attached to the amino of lysine in carbon e.
Biotin is a cofactor for 1) Pyruvate
carboxylase 2) ß-methylcrotonylCoA carboxylase 3)
Propionyl CoA carboxylase 4) Acetyl CoA
carboxylase
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So, after leaving the detour of biotin we return
to pyruvate carboxylase and gluconeogenesis
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The next step is the synthesis of
phosphoenolpyruvic acid from oxaloacetate
The synthesis of PEPA reverses the effect of
pyruvate kinase
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Gluconeogenesis takes place in the cytosol and in
the mitochondria. There are two pathways to
generate PEPA (phosphoenolpyruvic acid). In both
pathways NADH must be generated to allow the
activity of glyceraldehyde-3-phosphate
dehydrogenase in the reduction of
3-phosphoglyceric acid.
From PEPA to fructose-1,6-bisphosphate all the
steps are shared by glycolysis and
gluconeogenesis and are reversible.
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This graph represents the relationship between
the activity of both enzymes and the energy
status of a muscle cell.
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From previous page, we can see the relationship
between phosphofructokinase and
fructose-1,6-phosphatase
In this point we have a metabolic cycle or
futile cycle that wastes energy but provides
more leverage for regulation
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Integration of gluconeogenesis and glycolysis
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There is a fundamental difference between the
role of glycolysis in the peripheral organs and
the liver. In liver the role of glycolysis is to
make you FAT!!!! In muscle is to make you
run!!! Ethanol and fatty acids are not
glucogenic (odd number fatty acids contribute
insignificantly to gluconeogenesis). Glycerol,
the ketoacids of most amino acids, lactate and
pyruvate ARE glucogenic. Galactose, fructose,
etc are not glucogenic. They are monosaccharides
in equilibrium with glucose!
Warning whoever says that fatty acids with even
number of carbons are glucogenic will be
decapitated!