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DENTAL BIOCHEMISTRY 2015
LECTURE 10
GLUCONEOGENESIS
Michael Lea
Lecture Outline
• Function of gluconeogenesis and tissue
distribution
• Reaction sequence
• Rate-limiting steps
• Energy requirement
• Substrates and regulation of gluconeogenesis
• Suggested reading: Lippincott’s Biochemistry, 6th edition, pages
117-123
Function of gluconeogenesis and
tissue distribution
• Gluconeogenesis is the synthesis
of glucose from three carbon
precursors including lactate,
pyruvate and glycerol
• Gluconeogenesis occurs in the liver
and kidney
Reaction sequence
• The conversion of pyruvate to glucose occurs in a
series of eleven reactions.
• Seven of the reactions are catalyzed by enzymes that
are also used in glycolysis.
• The conversion of pyruvate to phosphenolpyruvate
occurs in two steps catalyzed by pyruvate
carboxylase and phosphoenolpyruvate
carboxykinase.
• Two specific phosphatases catalyze the hydrolysis of
fructose 1,6-bisphosphate and glucose 6-phosphate.
Rate-limiting Steps in
Gluconeogenesis
• Hormonal and dietary regulation is exerted on
the enzymes whose function is restricted to
gluconeogenesis : pyruvate carboxylase,
phosphoenolpyruvate carboxykinase,
fructose 1,6-bisphosphatase and glucose 6phosphatase.
• Activation of pyruvate carboxylase by acetyl
coenzyme A is an important regulatory
mechanism.
Energy Requirement
• The conversion of two moles of
pyruvate to one mole of glucose
requires the equivalent of 6 moles of
ATP and two moles of NADH.
X
ADP
ATP
Substrates for Gluconeogenesis
• Major substrates include lactate,
pyruvate and glycerol.
• Most amino acids can be metabolized to
form precursors for gluconeogenesis.
Reciprocal Control of Glycolysis and
Gluconeogenesis
• Insulin increases glycolysis and
decreases gluconeogenesis
• Glucocorticoids and glucagon increase
gluconeogenesis and decrease
glycolysis.
Reciprocal Control of Glycolysis and Gluconeogenesis
by Fructose 2,6-bisphosphate
• Fructose 2,6-bisphosphate (F26BP) is a switch
molecule that increases glycolysis by activating
phosphofructokinase 1 and inhibiting fructose 1,6bisphosphatase.
• F26BP levels are controlled by an enzyme with 2
active sites. The un-phosphorylated enzyme has
phosphofructokinase 2 activity and yields F26BP.
The phosphorylated enzyme has fructose 2,6bisphosphatase activity and lowers the concentration
of F26BP.
ADP
X
ATP
X
Gluconeogenesis and Diabetes
• In diabetes mellitus there is impaired uptake of
glucose, particularly in muscle and adipose tissue.
• The body responds as in starvation with an increase
in gluconeogenesis. This results in a further elevation
of blood glucose levels that may exceed the renal
glucose threshold resulting in significant glucose in
urine.
Lecture Objectives
• After studying this lecture material you should be able
to
• Describe the function of gluconeogenesis
• Identify where gluconeogenesis occurs
• Distinguish the enzyme catalyzed reactions common
to glycolysis and gluconeogenesis and those unique
to gluconeogenesis
• Identify the energy requirement for gluconeogenesis
• Describe the substrates and regulation of
gluconeogenesis