1. DENTAL BIOCHEMISTRY 2015 LECTURE 10 GLUCONEOGENESIS Michael Lea

2. 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

3. 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

4. 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.

8. 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.

9. 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.

10. ADP ATP X

11. Substrates for Gluconeogenesis Major substrates include lactate, pyruvate and glycerol. Most amino acids can be metabolized to form precursors for gluconeogenesis.

12. Reciprocal Control of Glycolysis and Gluconeogenesis Insulin increases glycolysis and decreases gluconeogenesis Glucocorticoids and glucagon increase gluconeogenesis and decrease glycolysis.

13. 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.

14. ATP ADP X X

15. 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.

16. 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