GLUCONEOGENESIS SLIDES medical school.pptx

Gluconeogenesis

1. HKMU DEPT. BIOCHEMISTRY AND MOLECULAR BIOLOGY : GLUCONEOGENESIS MD1& BScN1 – students The HKMU

2. DEFINITION: - Gluconeogenesis is the biosynthesis of new glucose, (NB: not glucose from glycogen). The production of glucose from other metabolites is necessary for use as a fuel source by the brain, testes, erythrocytes and kidney medulla . . The HKMU

3. During starvation, however, the brain can derive energy from ketone bodies which are converted to acetyl- CoA The HKMU

4. Synthesis of glucose from three and four carbon precursors is essentially a reversal of glycolysis with some by pass reactions The HKMU

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6. These by pass reactions are the pyruvate kinase , phosphofructokinase-1(PFK-1) and hexokinase/glucokinase catalyzed reactions The HKMU

7. In the liver or kidney cortex and in some cases skeletal muscle, the glucose-6-phosphate (G6P) produced by gluconeogenesis can be incorporated into glycogen. Since skeletal muscle lacks glucose-6-phosphatase it cannot deliver free glucose to the blood and undergoes gluconeogenesis exclusively as a mechanism to generate glucose for storage as glycogen The HKMU

8. Conversion of pyruvate to PEP requires the action of two mitochondrial enzymes. The first is an ATP-requiring reaction catalyzed by pyruvate carboxylase, (PC). As the name of the enzyme implies, pyruvate is carboxylated to form oxaloacetate (OAA) . The HKMU PYRUVATE TO PHOSPHOENOLPYRUVATE (PEP), BYPASS 1

9. The CO 2 in this reaction is in the form of bicarbonate (HCO 3 - ) . This reaction is an anaplerotic reaction since it can be used to fill-up the TCA cycle . The second enzyme in the conversion of pyruvate to PEP is PEP carboxykinase (PEPCK). The HKMU

10. PEPCK requires GTP in the decarboxylation of OAA to yield PEP. The HKMU

11. Fructose-1,6-bisphosphate (F1,6BP) conversion to fructose-6-phosphate (F6P) is the reverse of the rate limiting step of glycolysis. The reaction, a simple hydrolysis, is catalyzed by fructose-1,6-bisphosphatase (F1,6BPase). The HKMU FRUCTOSE-1,6-BISPHOSPHATE TO FRUCTOSE-6-PHOSPHATE, BYPASS 2

12. Like the regulation of glycolysis occurring at the PFK-1 reaction, the F1,6BPase reaction is a major point of control of gluconeogenesis The HKMU

13. G6P is converted to glucose through the action of glucose-6-phosphatase G6Pase). This reaction is also a simple hydrolysis reaction like that of F1,6BPase. Since the brain and skeletal muscle, as well as most non-hepatic tissues, lack G6Pase activity, any gluconeogenesis that occurs in these tissues is not utilized for blood glucose supply The HKMU GLUCOSE-6-PHOSPHATE (G6P) TO GLUCOSE (OR GLYCOGEN), BYPASS 3

14. In the kidney, muscle and especially the liver, G6P can be shunted toward glycogen if blood glucose levels are adequate . The HKMU

15. Lactate: Lactate is a predominate source of carbon atoms for glucose synthesis by gluconeogenesis. During anaerobic glycolysis in skeletal muscle, pyruvate is reduced to lactate by lactate dehydrogenase (LDH). The HKMU Glucogenic precursors

16. This reaction serves two critical functions during anaerobic glycolysis. First, in the direction of lactate formation the LDH reaction requires NADH and yields NAD + which is then available for use by the glyceraldehyde-3-phosphate dehydrogenase reaction of glycolysis . THESE TWO REACTION ARE, THEREFORE, INTIMATELY COUPLED DURING ANAEROBIC GLYCOLYSIS. The HKMU

17. Secondly, the lactate produced by the LDH reaction is released to the blood stream and transported to the liver where it is converted to glucose. The glucose is then returned to the blood for use by muscle as an energy source and to replenish glycogen stores. This cycle is termed the Cori cycle . The HKMU

18. The Cori cycle invloves the utilization of lactate, produced by glycolysis in non-hepatic tissues, (such as muscle and erythrocytes) as a carbon source for hepatic gluconeogenesis.. The HKMU

19. In this way the liver can convert the anaerobic byproduct of glycolysis, lactate, back into more glucose for reuse by non-hepatic tissues. The HKMU

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21. Pyruvate, generated in muscle and other peripheral tissues, can be transaminated to alanine which is returned to the liver for gluconeogenesis . The transamination reaction requires an a -amino acid as donor of the amino group, generating an a -keto acid in the process The HKMU Pyruvate:

22. This pathway is termed the glucose-alanine cycle . Although the majority of amino acids are degraded in the liver some are deaminated in muscle. The glucose-alanine cycle is, therefore, an indirect mechanism for muscle to eliminate nitrogen while replenishing its energy supply. The HKMU

23. However, the major function of the glucose-alanine cycle is to allow non-hepatic tissues to deliver the amino portion of catabolized amino acids to the liver for excretion as urea. Within the liver the alanine is converted back to pyruvate and used as a gluconeogenic substrate (if that is the hepatic requirement) or oxidized in the TCA cycle. The amino nitrogen is converted to urea in the urea cycle and excreted by the kidneys. The HKMU

24. The glucose-alanine cycle is used primarily as a mechanism for skeletal muscle to eliminate nitrogen while replenishing its energy supply. Glucose oxidation produces pyruvate which can undergo transamination to alanine. This reaction is catalyzed by alanine transaminase, ALT (ALT used to be referred to a serum glutamate-pyruvate transaminase, SGPT). The HKMU

25. Additionally, during periods of fasting, skeletal muscle protein is degraded for the energy value of the amino acid carbons and alanine is a major amino acid in protein. The alanine then enters the blood stream and is transported to the liver. The HKMU

26. Within the liver alanine is converted back to pyruvate which is then a source of carbon atoms for gluconeogenesis. The newly formed glucose can then enter the blood for delivery back to the muscle. The amino group transported from the muscle to the liver in the form of alanine is converted to urea in the urea cycle and excreted. The HKMU

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28. Amino Acids: All 20 of the amino acids, excepting leucine and lysine, can be degraded to TCA cycle intermediates The HKMU

29. This allows the carbon skeletons of the amino acids to be converted to those in oxaloacetate and subsequently into pyruvate. The pyruvate thus formed can be utilized by the gluconeogenic pathway. When glycogen stores are depleted, in muscle during exertion and liver during fasting, catabolism of muscle proteins to amino acids contributes the major source of carbon for maintenance of blood glucose levels The HKMU

30. The glycerol backbone of lipids can be used for gluconeogenesis. This requires phosphorylation to glycerol-3-phosphate by glycerol kinase and dehydrogenation to dihydroxyacetone phosphate (DHAP) by glyceraldehyde-3-phosphate dehydrogenase(G3PDH). The HKMU Glycerol