Gluconeogenesis

Lecture 21

BCMB 401 Fall 23

Reading: Chapter 16.4

 Gluconeogenesis

➢ The synthesis of glucose from

noncarbohydrate precursors.
➢ Done primarily in the liver
➢ The major precursors for
gluconeogenesis are lactate, amino
acids, and glycerol.
➢ Lactate from lactic acid
fermentation
➢ Amino acids from protein
breakdown for energy production
in muscle. Alanine (pyruvate)
➢ Amino acids from protein
breakdown during starvation
➢ Glycerol from fat breakdown
➢ Provides glucose for the
bloodstream during fasting or
starvation
Gluconeogenesis

➢ Seven reactions in gluconeogenesis are the reverse

reactions from glycolysis, catalyzed by the same enzymes

➢ The three irreversible, regulated steps must be bypassed

using different reactions
Pyruvate Carboxylase
➢ Pyruvate
carboxylase
reaction occurs in
the mitochondria
➢ Requires biotin, a
covalently attached
prosthetic group,
which serves as
the carrier of CO2
Oxaloacetate is Shuttled to the Cytoplasm and
Converted to Phosphoenolpyruvte

➢ In the mitochondria, Oxalaoacetate is reduced to malate in a

reaction catalyzed by malate dehydrogenase
➢ Malate is transported out of the mitochondria to the
cytoplasm where it is oxidized to oxaloacetate by
cytoplasmic malate dehydrogenase
➢ Oxaloacetate is then decarboxylated and phosphorylated
(using GTP) by phosphoenolpyruvate carboxykinase
(PEPCK)
➢ One ATP (pyruvate carboxylase) and one GTP (PEP
carboxykinase are required to convert pyruvate to
phosphoenolpyruvate
 Gluconeogenesis

➢ Phosphoenolpyruvate is
converted to fructose 1,6-
bisphosphate by reversible
reactions from glycolysis
Fructose 1,6-bisphosphatase and Glucose 6-phosphatase

➢ The allosteric enzyme fructose 1,6-bisphosphatase catalyzes the

hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate and Pi.
Fructose 1,6-bisphosphate + H2O ⎯⎯⎯⎯⎯⎯⎯⎯⎯
Fructose 1,6-bisphosphatase
→
fructose 6-phosphate + Pi

➢ Glucose 6-phosphatase converts glucose 6-phosphate to glucose to be

transported into the bloodstream
➢ Located in the endoplasmic reticulum (membrane)
➢ Glucose 6-phosphate is transported into the lumen of the ER.
➢ Glucose 6-phosphatase hydrolyzes glucose 6-phosphate to glucose.
➢ Glucose and Pi are shuttled back to the cytoplasm by transporters.
 Gluconeogenesis

➢ The synthesis of glucose from

noncarbohydrate precursors is very
energetically costly.
➢ 6 ATP equivalents (4 ATP + 2 GTP) to
convert two molecules of pyruvate to one
molecule of glucose
➢ Normally a supplemental pathway to
provide glucose for the blood stream
using primarily lactate and glycerol
➢ Becomes primary pathway for the liver to
provide glucose for bloodstream during
starvation.

2 Pyruvate + 4 ATP + 2 GTP + 2 NADH + 6 H2O →

glucose + 4 ADP + 2 GTP + 6 Pi + 2 NAD+ + 2 H+
(
G = −48 kJ mol−1 −11kcal mol−1 )
 The Cori cycle. Lactate formed by Cardiac Muscle. Lactate
active muscle is converted into can be converted back to
glucose by the liver. pyruvate.

➢ Lactate produced by muscle during

fermentation is released into the blood.
➢ Liver removes the lactate and converts
it into glucose, which can be released
into the blood.
➢ In cardiac muscle cells: Lactate can
➢ Use of amino acids for fuel by muscle also be converted to pyruvate and
produces alanine that is released into used for energy production.
blood, taken up by liver and used to
produce glucose by gluconeogenesis