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 6-phosphatase.

• 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.

ADPATPX

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 1,6-bisphosphatase.

• 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 2,6-bisphosphatase activity and lowers the concentration of F26BP.

ATPADPX 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