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, 6 th 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.

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 (F 26 BP) is a switch molecule that increases glycolysis by activating phosphofructokinase 1 and inhibiting fructose 1, 6 bisphosphatase. • F 26 BP levels are controlled by an enzyme with 2 active sites. The un-phosphorylated enzyme has phosphofructokinase 2 activity and yields F 26 BP. The phosphorylated enzyme has fructose 2, 6 bisphosphatase activity and lowers the concentration of F 26 BP.

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