1. Dr.S.Chakravarty MD

3. Gluconeogenesis is the process of synthesizing glucose or glycogen from non-carbohydrate precursors.

4. Gluconeogenesis meets the needs of the body for glucose when insufficient carbohydrate is available from the diet or glycogen reserves. A supply of glucose is necessary especially for the nervous system and erythrocytes. Glucose is also important in maintaining the level of intermediates of the citric acid cycle even when fatty acids are the main source of acetyl-CoA in the tissues. Gluconeogenesis clears lactate produced by muscle and erythrocytes and glycerol produced by adipose tissue. In ruminants, propionate is a product of rumen metabolism of carbohydrates, and is a major substrate for gluconeogenesis. Failure of gluconeogenesis is usually fatal. Hypoglycemia causes brain dysfunction, which can lead to coma and death.

5. Tissues :- Liver and Kidney are the major gluconeogenic tissues, but the small intestine may also be a source of glucose in the fasting state. Subcellular site :- Partly mitochondrial and partly cytosolic.

7. α-ketoglutarate Glutamate Alanine Pyruvate α-ketoglutarate Glutamate Aspartate Oxaloacetate Alanine transaminase (ALT) Aspartate transaminase (ALT)

8. Entry points of Glucogenic amino acids

9. Lactate NAD + NADH + H + Lactate Pyruvate Lactate Dehydrogenase (LDH) USMLE! Remember :-Conversion of Lactate to pyruvate requires NAD and not NADH

11. Glycerol ATP ADP Glycerol Glycerol 3 –P This enzyme is absent in adipose tissue. Glycerol kinase

12. Conversion of Glycerol to Glucose: Triglycerides Glycerol Fatty acids  Beta oxidation Acetyl Co- A Liver Glycerol 3- PO4 Dihydroxyacetone phosphate Glycerol kinase Glycerol-3-po4 dehydrogenase NAD+ NADH FASTING OR LOW GLUCOSE

13. Propionate – From oxidation of odd chain fatty acids

14. The pathway Thermodynamic Barriers Prevent a Simple Reversal of Glycolysis. Three nonequilibrium reactions in glycolysis catalyzed by hexokinase, phosphofructokinase and pyruvate kinase, prevent simple reversal of glycolysis for glucose synthesis.

15. Pyruvate Oxaloacetate Phosphoenol pyruvate ATP GTP ADP GDP Pyruvate carboxylase Phosphoenolpyruvate carboxykinase Energy derived from fatty acid oxidation GTP derived from succinate thoikinase Step 1: (Mitochondria) (cytosol) CO2 Problem --Mitochondrial membrane is impermeable to OAA!! USMLE CONCEPT!!! ABC carboxylase BIOTIN

16. Oxaloacetate Malate Oxaloacetate Mitochondria cytosol Malate dehydrogenase NAD NADH NAD NADH

17. The next few steps are reversal of Glycolysis till Fructose 1,6 bisphosphate is formed.

18. Fructose -6-PO4 Fructose 1,6 Bisphosphate PFK -1 Fructose 1,6 bisphosphatase ADP, AMP (+) ATP (-) Fructose 2,6 Bisphosphate (+) Fructose 2,6 Bisphosphate Step 2: Conversion of fructose 1,6 bisphosphate to fructose 6-PO-4 (+) Gluconeogenesis Glycolysis Glucose Pyruvate

19. Step 3: Conversion to Glucose Glucose Glucose-6-po4 Glucose-6- phosphatase Glucokinase Glycolysis Gluconeogenesis ATP ADP PO4

20. 1.Pyruvate & Phosphoenolpyruvate Fructose 1,6- Bisphosphate & Fructose 6-Phosphate Glucose 6-Phosphate & Glucose & Glucose to glycogen(not shown) GLUCONEOGENESIS

21. Glycolysis and Gluconeogenesis are regulated reciprocally. Regulation Induction / Repression Covalent modification Allosteric

22. Induction & Repression of Key Enzymes Requires Several Hours.

23. Table 20.1 Harper 29 th page 190

24. Glucagon and epinephrine inhibit glycolysis and stimulate gluconeogenesis in the liver by increasing the concentration of cAMP. cAMP cAMP-dependent protein kinase phosphorylation and inactivation of pyruvate kinase. They also affect the concentration of fructose 2,6- bisphosphate which is the most potent positive allosteric effector of of Phosphofructokinase -1 and inhibitor of Fructose 1,6 bisphosphatase.

25. Fructose -6-po4 Fructose -1,6- Bisphosphate Fructose -2,6- Bisphosphate PFK-1 PFK-2 Insulin Glucagon Regulation of PFK -1 : USMLE concept!!!

26. Pyruvate Acetyl Co-AOxaloacetate Pyruvate dehydrogenase Pyruvate Carboxylase (-) (+) Acetyl Co-A is the allosteric activator of pyruvate carboxylase What is the source of acetyl Co-A during starvation ? Glucagon (+)Source of pyruvate ? = allosteric regulation

27. Acetyl -CoA as an is an allosteric activator of Pyruvate carboxylase. Phosphofructokinase (phosphofructokinase-1 )is inhibited by citrate and by normal intracellular concentrations of ATP and is activated by 5'AMP. (5'AMP acts as an indicator of the energy status of the cell. ) – When ATP is used AMP increases  sensitive signal for energy state of the cell.

28. ALCOHOL DEHYDROGENASE Alcohol  Acetaldehyde  Acetate Excess NADH  – EXCESS LACTATE from PYRUVATE – Excess Malate FROM OAA – Excess Glycerol 3 P from DHAP –  No or less Gluconeogenesis!!  Hypoglycemia NAD NADH

29. Immediately after completing a 25-mile marathon race, a healthy 24-yr old man was extremely dehydrated and thirsty. He quickly consumed a 6- pack of ice-cold beer and shortly thereafter became very weak and light-headed and nearly fainted. He complained of muscle cramping and pain. What is the most probable cause ? 1.Excess lactate in blood 2.Excess Alcohol in blood 3.Excess NADH 4.Dehydration 5.Electrolyte imbalance

30. Which of the following enzymes can be induced genetically by hormones in a person with prolonged history of fasting? A.Glucokinase B.Pyruvate Carboxylase C.PFK-1 D.Acetyl co-A Carboxylase E.Phosphofructokinase

31. In the citric acid cycle, succinate thiokinase catalyzes the cleavage of the succinyl –Co-A to succinate with formation of a high energy compound. This compound can then be used by the body in which of the following biochemical pathways? – Oxidative phosphorylation – Gluconeogenesis – Formation of creatine phosphate – Cholesterol synthesis – Fatty acid synthesis