Biochemistry: A Short Course
Tymoczko • Berg • Stryer
© 2013 W. H. Freeman and Company
Chapter 17 Outline
Gluconeogenesis is the synthesis of glucose from noncarbohydrate precursors.
The major site of gluconeogenesis is the liver, although gluconeogenesis can
occur in the kidney.
Gluconeogenesis is especially important during fasting or starvation, as
glucose is the primary fuel for the brain and the only fuel for red blood cells.
The gluconeogenic pathway converts pyruvate into glucose.
Pyruvate can by formed from muscle‐derived lactate in the liver by lactate dehydrogenase.
The carbon skeletons of some amino acids can be converted into gluconeogenic intermediates.
Glycerol, derived from the hydrolysis of triacylglycerols, can be converted into dihydroxyacetone
phosphate, which can be processed by gluconeogenesis or glycolysis.
The three irreversible steps in glycolysis must be bypassed in gluconeogenesis.
The formation of phosphoenolpyruvate from pyruvate requires two enzymes. The
sum of the two reactions is:
Pyruvate carboxylase requires the vitamin biotin as a
cofactor. The formation of oxaloacetate by pyruvate
carboxylase occurs in three stages.
The formation of oxaloacetate by pyruvate carboxylase occurs in the
Oxaloacetate is reduced to malate and transported into the cytoplasm, where it
is reoxidized to oxaloacetate with the generation of cytoplasmic NADH.
PEP is then synthesized from oxaloacetate by phosphoenolpyruvate
Phosphoenolpyruvate is metabolized by the enzymes of glycolysis in the reverse
direction until the next irreversible step, the hydrolysis of fructose 1,6‐bisphosphate.
The enzyme catalyzing this reaction is fructose 1,6‐bisphosphatase, an allosteric
The generation of free glucose, which occurs essentially only in the liver, is
the final step in gluconeogenesis.
Glucose 6‐phosphate is transported into the lumen of the endoplasmic
Glucose 6‐phosphatase, an integral membrane on the inner surface of the
endoplasmic reticulum, catalyzes the formation of glucose from glucose 6‐
Gluconeogenesis and glycolysis are regulated so that
within a cell, one pathway is relatively inactive while
the other is highly active.
The rationale for reciprocal regulation is that glycolysis will predominate when glucose
is abundant, and gluconeogenesis will be highly active when glucose is scarce.
The interconversion of fructose 1,6‐bisphosphate and fructose 6‐phosphate is a
key regulatory site.
Additionally, glycolysis and gluconeogenesis are reciprocally regulated at the
interconversion of phosphoenolpyruvate and pyruvate.
If ATP is required, glycolysis predominates. If glucose is required, gluconeogenesis
In liver, the rates of glycolysis and gluconeogenesis are adjusted to maintain blood
The key regulator of glucose metabolism in liver is fructose 2,6‐bisphosphate.
Fructose 2,6‐bisphosphate stimulates phosphofructokinase and inhibits fructose
The kinase that synthesizes fructose 2,6‐bisphosphate and the phosphatase that
hydrolyzes this molecule are located on the same polypeptide chain. Such an
arrangement is called a bifunctional enzyme.
Which activity of the bifunctional enzyme is determined by blood glucose
When blood glucose is low, the hormone glucagon is secreted.
The glucagon signaling pathway leads to the phosphorylation of the
bifunctional enzyme, which inhibits the kinase and stimulates the
Insulin normally inhibits gluconeogenesis. In type
2 diabetes, insulin fails to act, a condition called
The enzymes of gluconeogenesis, especially
PEPCK, are active leading to abnormally high
levels of blood glucose.
Exercise and diet can enhance insulin sensitivity.
Substrate cycles can increase the flux down a metabolic pathway.
Muscle and liver display inter‐organ cooperation in a
series of reactions called the Cori cycle.
Lactate produced by muscle during contraction is
released into the blood.
Liver removes the lactate and converts it into glucose,
which can be released into the blood.