Metabolic integration and Regulation

Transcription

1 Metabolic integration and Regulation : Graduate Biochemistry Trimester 2/2016 Assistant Prof. Dr. Panida Khunkaewla School of Chemistry Suranaree University of Technology 1

2 Overview of metabolism Degradation Synthesis Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

3 Integration of Metabolic pathways 3

4 Catabolism of proteins, fats, and carbohydrates 4

5 5

6 Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

7 Specialized Metabolic Functions of Mammalian Tissues 7

8 8

9 Metabolic pathways for glucose 6-phosphate in the liver Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

10 Amino acid Metabolism Amino acids from cell breakdown Amino acids from diet Synthesis of body proteins for cell structure and other needed components, such as enzymes hormones, and muscle contractile proteins Energy production from amino acid carbon skeletons for body cells: yield on averages 4 kcal/g Amino acid pool in cell Free NH 3 Synthesis of nonprotein nitrogen-containing compound e.g. serotonin Fat made from amino acid carbon skeletons (liver cells only, and generally not much) Glucose production from amino acid carbon skeletons (liver and kidney cells only) Urea synthesis in live Excretion of urea by the kidneys

11 Metabolism of Amino Acid in The Liver Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

12 12

13 Metabolism of Fatty Acids in The Liver Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

14 Acetyl CoA is central in energy metabolism 14

15 Key concept of metabolic integration Metabolic pathway are controlled in different nutritional and disease states to maintain sources of energy and amino acids in the blood for all tissues. Pathways that remove excess fuels from the blood (glycogenesis, glycolysis, fatty acid synthesis and lipogenesis) are active in the fed state. Pathways that maintain adequate levels of fuel in the blood (glycogenolysis, gluconeogenesis, lipolysis, proteolysis, and ketogenesis) are active in the starved state. Pathways are controlled by substrate availability, allosteric effectors, covalent modification, and induction or repression of key enzymes. The changes in metabolism that accompany common disease state are variations on the 15 themes that function in the fed and fasted states

16 Metabolic control In a steady state An equal rate of Formation and consumption of intermediates Perturbation alters the rate Changing of enzyme activities The system returns to the steady state. 16

17 Regulatory mechanisms maintain constant level of key metabolites ATP, ADP, AMP and NADH in cells glucose in the blood matching the use or storage of glycogen to the organism s changing needs. 17

18 Metabolic regulation Enzymes activities (Fast metabolic adjustment) Allosteric Covalent modification Feedback inhibition regulation Hormones or growth factor (Slow metabolic adjustment) covalent modification changing of enzyme synthesis or enzymes activities 18

19 Factors that determine the activity of an enzyme signal Association with regulatory protein Sequestration (compartmentation) DNA transcription translation turnover mrna Enzyme Amino acids nucleotides Allosteric regulation Covalent modification 19

20 Glycolysis and Gluconeogenesis pathway Hexokinase Phosphofrucokinase-1 Fructose 1,6-bisphosphatase Pyruvate kinase Pyruvate carboxylase 20

21 Regulation of pyruvate kinase Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed., 2005 This mechanism prevents the liver from consuming glucose by glycolysis when the blood glucose concentration is low 21

22 Glycogen synthesis Glycogen phosphorylase is regulated allosterically and homonally GSK3 = Glycogen synthase kinase-3 Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

23 Effects of GSK3 on glycogen synthase activity Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

24 Control of glycogen synthesis from blood glucose in myocytes Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

25 Classes of Hormones Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

26 Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

27 Regulation of carbohydrate metabolism in hepatocyte; during high blood glucose Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

28 Some of genes regulated by insulin Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

29 The well-fed state Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

30 Glucose regulation of insulin secretion by pancreatic cells Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

31 The Fasting State Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

32 What happen in the first week of starvation? Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

33 The five phases of glucose homeostasis Textbook of Biochemistry with Clinical Correlations, 7e edited by Thomas M. Devlin 2011 John Wiley & Sons, Inc. 33

34 Regulation of carbohydrate metabolism in hepatocyte; during high blood glucose Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed.,

35 Substrate and hormone level in blood of well-fed, fasting, and starving human Textbook of Biochemistry with Clinical Correlations, 7e edited by Thomas M. Devlin 2011 John Wiley & Sons, Inc. 35

36 Fuel metabolism in the liver during prolonged fasting or in uncontrolled diabetes mellitus 36

37 Metabolic interrelationships of tissues in type 1 diabetes mellitus. Textbook of Biochemistry with Clinical Correlations, 7e edited by Thomas M. Devlin 2011 John Wiley & Sons, Inc. Type I diabetes: insulin-dependent diabetes (requires insulin to live) begins before age 20 caused by autoimmune destruction of -cells Hyperglycemia: The inability of the insulindependent tissues to take up plasma glucose accelerated hepatic gluconeogenesis from amino acids derived from muscle protein Hyperlipoproteinemia (chylomicrons and VLDLs) Low lipoprotein lipase activity in adipose tissue capillaries (an enzyme dependent on insulin for its synthesis) Severe ketoacidosis.: Increase of lipolysis in the adipose tissue and accelerated fatty acid oxidation in the liver. Glucose excreted into urine leads water excreted -> feel hungry + thirsty 37

38 Metabolic interrelationships of tissues in type 2 diabetes mellitus. Textbook of Biochemistry with Clinical Correlations, 7e edited by Thomas M. Devlin 2011 John Wiley & Sons, Inc. Hyperglycemia, often with hypertriglyceridemia. The ketoacidosis characteristic of the insulin-dependent disease is not observed. Increased levels of VLDL are probably the result of increased hepatic triacylglycerol synthesis stimulated by hyperglycemia and hyperinsulinemia. 38

39 Relevant of manipulation of metabolic pathway Drug design to treat diseases Genetic engineering of organisms of biotechnological interest Genetic syndromes therapy 39