1. MBG304 Biochemistry Lecture 7: Gluconeogenesis Hikmet Geçkil, Professor Department of Molecular Biology and Genetics Inonu University

2. Gluconeogenesis is the name for metabolic pathways that result in the generation of glucose from non-carbohydrate substrates such as pyruvate, lactate, glycerol, and glucogenic amino acids. Gluconeogenesis is one of the two main mechanisms used by humans and many other animals to maintain blood glucose levels, avoiding low blood glucose level (hypoglycemia). The other means of maintaining blood glucose levels is through the degradation of glycogen (glycogenolysis). Lecture 7: Gluconeogenesis MBG304 Biochemsitry/Hikmet Geçkil

3. Lecture 7: Gluconeogenesis MBG304 Biochemsitry/Hikmet Geçkil

4. In humans the main gluconeogenic precursors are: – Lactate – Glycerol – Alanine – Glutamine – They account for over 90% of the overall gluconeogenesis. Lecture 7: Gluconeogenesis MBG304 Biochemsitry/Hikmet Geçkil

5. Lactate is transported back to the liver where it is converted into pyruvate by the Cori cycle using the enzyme lactate dehydrogenase. Pyruvate can then be used to generate glucose. Transamination or deamination of amino acids facilitates entering of their carbon skeleton into the cycle directly (as pyruvate or oxaloacetate), or indirectly via the citric acid cycle. Lecture 7: Gluconeogenesis MBG304 Biochemsitry/Hikmet Geçkil

6. Many of the reactions gluconeogenesis are the reversible steps found in glycolysis. In glycolysis there are three highly exergonic steps (steps 1,3,10) and these are also regulatory steps which include the enzymes hexokinase, phosphofructokinase, and pyruvate kinase. Lecture 7: Gluconeogenesis MBG304 Biochemsitry/Hikmet Geçkil

7. Irreversible steps Lecture 7: Gluconeogenesis Glucose 6-phosphatase (reaction 1) Fructose 1,6-biphosphatase (rection3) Pyruvate carboxylase (pyruvate  oxaloacetate) and then Phosphoenol pyruvate carboxykinase (oxaloacetate  phosphosenol pyruvate) (reaction 10) MBG304 Biochemsitry/Hikmet Geçkil

8. – It begins in the mitochondria with the formation of oxaloacetate by the carboxylation of pyruvate in a reaction that requires one molecule of ATP, and is catalyzed by pyruvate carboxylase. – Oxaloacetate is reduced to malate using NADH, a step required for its transportation out of the mitochondria. – Malate is oxidized to oxaloacetate using NAD + in the cytosol, where the remaining steps of gluconeogenesis take place. – Oxaloacetate is decarboxylated and then phosphorylated to form phosphoenolpyruvate. – The next steps in the reaction are the same as reversed glycolysis. Lecture 7: Gluconeogenesis MBG304 Biochemsitry/Hikmet Geçkil

9. Lecture 7: Gluconeogenesis MBG304 Biochemsitry/Hikmet Geçkil

10. Gluconeogenesis- ANIMATED Lecture 7: Gluconeogenesis MBG304 Biochemsitry/Hikmet Geçkil