Gluconeogenesis Lecture Notes PDF

Lippincott’s illustrated reviews Chapter 10 – Page 117 Lecture 22 Gluconeogenesis 1  Specific Objectives By the end of this lecture students can be able to: Understand the function of gluconeogenesis process. Explain the most important substrates for...

Lippincott’s illustrated reviews Chapter 10 – Page 117 Lecture 22 Gluconeogenesis 1  Specific Objectives By the end of this lecture students can be able to: Understand the function of gluconeogenesis process. Explain the most important substrates for gluconeogenesis process. Discuss the major regulating substances for gluconeogenesis process. 2  Overview Some tissues, such as brain, red blood cells, kidney medulla, lens and cornea of the eye, testes, and exercising muscle, require a continuous supply of glucose as a metabolic fuel. During Fasting and sleep Liver glycogen, an essential postprandial source of glucose, can meet these needs for only 10-18 hours in the absence of dietary intake of carbohydrate. 3  During prolonged fast, gluconeogenesis can take place. In this process, glucose formed from precursors such as lactate, pyruvate, glycerol (derived from the backbone of triacylglycerols), and α-keto acid (derived from the catabolism of glucogenic amino acids). It requires both mitochondria and cytosolic enzymes. 4 5  During an overnight fast, approximately 90% of gluconeogenesis occurs in liver, with the kidney providing 10% of the newly synthesis of glucose molecules. However, during prolonged fasting, the kidney become major glucose-producing organs, contributing an estimated 40% of the total glucose production. 6  Substrates for Gluconeogenesis Gluconeogenic precursors are molecules that can be used to produce a net synthesis of glucose. Break down They include intermediates of glycolysis and the tricarboxylic acid (TCA) cycle. without the pyurate Glycerol, lactate, and the α-keto acids obtained from the transamination of glucogenic amino acids are the important gluconeogenic precursors. 7 A. Glycerol Glycerol is released during the hydrolysis of triacylglycerols in adipose tissue, and is delivered by the blood to the liver. use energy 8 B. Lactate Lactate is released into the blood by exercising skeletal muscle, and by cell that lack mitochondria, such as red blood cells. In the Cori’s cycle, blood borne glucose is converted by exercising muscle to lactate, which diffuses into the blood. Blood filled with glucose Exorsingmucle Lactate Diffuse into bloo realsed to blood glucose This lactate is taken up by the liver and takeyy by reconverted to glucose, which is released back into the circulation. 9 Note: The muscle cramps, often associated with strenuous muscular exercise, are through to be due to lactate accumulation. 10 C. Amino acids Amino acids derived from hydrolysis of tissue proteins are the major sources of glucose during a fast. 11  α-keto acids, such as α-keto glutarate, are derived from the metabolism of glucogenic amino acid. These α-keto acids can enter the TCA cycle and form oxaloacetate (OAA)- a direct precursor of phosphoenol pyruvate (PEP). Enzyme that will help 12 13  Regulation of Gluconeogenesis Key enzymes for gluconeogenesis are: 0 PEP-carboxykinase Fructose-1 ,6 bisphosphatase Glucose-6-phosphatase Short note 1 PEP carboxy kinase 2 Fractuse 1 6 biphosphate 3 Glucose 6 Phosphate 14 A. Glucagon This hormone from the α cell of pancreatic islets stimulates gluconeogenesis as follow: 1. Glucagon activate fructose 1,6-bisphosphatase 2. Increases the transcription of the gene for PEP-carboxykinase. 15  Insulin causes decreased transcription of the mRNA for this enzyme. i 2 3 4 16 B. Substrate availability The availability of gluconeogenic precursors, particularly glucogenic amino acids, significantly influences the rate of hepatic glucose synthesis. Insulin inhibit mobilization of amino acid from tissue protein. 17 C. Allosteric activation by acetyl CoA: During fasting lipolysis increased in adipose tissues so liver is flooded by fatty acids which undergo β- oxidation. accumulation of acetyl CoA activates the hepatic pyruvate carboxylase. D. Allosteric inhibition by AMP Fructose 1,6-bisphosphatase is inhibited by AMP- a compound that activates phosphofructokinase-1 which regulates glycolysis and gluconeogenesis. 18 Reference Book: Champe, P. C., Harvey, R. A. and Ferrier, D. R., 2005. Biochemistry “Lippincott’s Illustrated Reviews”, 5th or 6th Edition 19