1. INTRODUCTION TO METABOLISM BATCH 17 MBBS Year 1 Element 5 17 th January 2012 Dr Girish Prabhu M.D Associate Professor AUFOM

2. Lecture 1: Introduction to metabolism Objectives: The objective of this lecture is to define and explain metabolism, differentiate between anabolism and catabolism and provide an overview of carbohydrate metabolism. Learning Outcomes: At the end of the lecture, students should be able to: – Define metabolism. – Distinguish between anabolism and catabolism. – Explain the principal characteristics of metabolic pathways – Give an overview of carbohydrate metabolism.

3. Definition Define metabolism Metabolism is defined as the sum total of all the chemical reactions that are taking place in the body. Metabolism is the overall process through which living systems acquire and utilize the free energy they need to carry out their various functions. Metabolism is derived from a Greek word, metabellin, which means “ to change”.

4. Definition Define Metabolic pathway Metabolic pathways are series of consecutive enzymatic reactions that produce specific products. What are Metabolites ? The reactants, intermediates, and products of metabolic pathways are referred to as metabolites

5. Definition The reaction pathways that comprise metabolism are often divided into two categories: 1. Catabolism, or degradation, in which nutrients and cell constituents are broken down exergonically to salvage their components and/or to generate free energy. 2. Anabolism, or biosynthesis, in which biomolecules are synthesized from simpler components. Some pathways serve both in catabolism and anabolism, such pathways are Amphibolic.

6. Metabolism Anabolism and catabolism are interrelated in that the products of one provide the substrates of the other. Many metabolic intermediates are shared between the two processes, and the precursors needed by anabolic pathways are found among the products of catabolism. Anabolism and catabolism are not necessarily balanced - one or the other may predominate in certain cells or at different times depending on cell needs

8. Types of Metabolic pathways

9. Why study metabolism ?

10. A knowledge of normal metabolism is essential for an understanding of abnormalities underlying disease. Normal metabolism includes adaptation to periods of starvation, exercise, pregnancy, and lactation. Abnormal metabolism may result from nutritional deficiency, enzyme deficiency, abnormal secretion of hormones, or the actions of drugs and toxins.

11. Free Energy Changes in Metabolism Overall  G is negative (-) for catabolic processes example: higher energy A  B  C  D  E lower energy compound G 1 compound G 2  G = G 2 - G 1 is negative

12. for an anabolic process, the  G is positive example: W  V  U  S  P Must supply energy, usually from ATP, to drive W  P to make the overall  G is negative So generally catabolic processes generate energy for anabolic processes Free Energy Changes in Metabolism

13. Characteristics of metabolism 1.Metabolic reactions are interdependent and interconnected. 2.They do not occur in isolation or in a random manner, rather they are organized into multi step sequences called metabolic pathways. In these pathways the product of one reaction serves as a substrate for the next one; and so on.

14. A striking characteristic of degradative metabolism is that it converts large numbers of diverse substances (carbohydrates, lipids, and proteins) to common intermediates. These intermediates are then further metabolized in a central oxidative pathway that terminates in a few end products. Characteristics of metabolism

15. Biosynthesis carries out the opposite process. Relatively few metabolites, mainly pyruvate, acetyl-CoA, and the citric acid cycle intermediates, serve as starting materials for a host of varied biosynthetic products. Characteristics of metabolism

16. Metabolic pathways are irreversible A highly exergonic reaction (having a large negative free energy change) is irreversible; that is, it goes to completion. If such a reaction is part of a multistep pathway, it confers directionality on the pathway; that is, it makes the entire pathway irreversible. Characteristics of metabolism

17. Catabolic and anabolic pathways must differ. If two metabolites are metabolically interconvertible, the pathway from the first to the second must differ from the pathway from the second back to the first. The existence of independent interconversion routes, is an important property of metabolic pathways because it allows independent control of the two processes. Characteristics of metabolism

18. Every metabolic pathway has a first committed step. Although metabolic pathways are irreversible, most of their component reactions function close to equilibrium. Early in each pathway, however, there is an irreversible(exergonic) reaction that “commits” the intermediate it produces to continue down the pathway. Characteristics of metabolism

19. Pathway Throughput Is Regulated by Controlling Enzymes Operating Far from Equilibrium Most enzymes in a metabolic pathway operate near equilibrium and therefore have net rates that are sensitive only to their substrate concentrations. Certain enzymes, which are strategically located in a metabolic pathway, operate far from equilibrium. Changes in substrate concentrations therefore have relatively little effect on the rate of the reaction because the enzyme is close to saturation. Only changes in the activity of the enzyme can significantly alter this rate. Substrate flux (rate of flow) is controlled by varying its activity. These enzymes, which are targets for metabolic regulation by allosteric interactions and other mechanisms, are responsible for the maintenance of a stable steady-state flux of metabolites through the pathway. This situation maximizes the pathway’s thermodynamic efficiency.

20. Metabolic pathways are regulated at several levels, from within the cell and from outside 1.The most immediate regulation is by the availability of substrate; when the intracellular concentration of an enzyme’s substrate is near or below Km (as is commonly the case), the rate of the reaction depends strongly upon substrate concentration. Characteristics of metabolism

21. 2.Metabolic activities of different tissues are regulated and integrated by growth factors and hormones. This regulation occurs virtually instantaneously (sometimes in less than a millisecond) through changes in the levels of intracellular messengers that modify the activity of existing enzyme molecules by allosteric mechanisms or by covalent modification such as phosphorylation. In other cases, the extracellular signal changes the cellular concentration of an enzyme by altering the rate of its synthesis or degradation, so the effect is seen only after minutes or hours. Characteristics of metabolism

22. Metabolic pathways are regulated 3.In order to exert control on the flux of metabolites through a metabolic pathway, it is necessary to regulate its rate-limiting step. The first committed step, being irreversible, functions too slowly to permit its substrates and products to equilibrate. The first committed step is often one of its rate-limiting steps. 4.This is an efficient way to exert control because it prevents the unnecessary synthesis of metabolites further along the pathway when they are not required. Characteristics of metabolism

23. Metabolic pathways in eukaryotic cells occur in specific cellular locations. Characteristics of metabolism

24. Virtually All Organisms Have the Same Basic Set of Metabolic Pathways. Modes of Enzyme Organization in Metabolic Pathways (a) Physically separate, soluble enzymes with diffusing intermediates. (b) A multienzyme complex. Substrate enters the complex, becomes covalently bound and then sequentially modified by other enzymes before product is released. No intermediates are free to diffuse away. (c) A membrane bound multienzyme system. Characteristics of metabolism

25. Modes of Enzyme Organization in Metabolic Pathways A membrane- bound multienzyme system Physically separate, soluble enzymes A multienzyme complex

26. Overview of carbohydrate Metabolism

27. Carbohydrate Metabolism Carbohydrate metabolism is centered on provision and fate of glucose. Glucose is the major component of carbohydrates. Metabolism of glucose to pyruvate or lactate takes place in all mammalian cells by a process called glycolysis. Glucose can be metabolized by glycolysis even in the absence of oxygen, when the end product is lactate.

28. Those tissues, which can utilize oxygen, are able to metabolize pyruvate to acetyl CoA, which can enter the citric acid cycle or tricarboxylic acid cycle (TCA cycle) for complete oxidation to CO 2 and H 2 O, with trapping of free energy as ATP in the process of oxidative phosphorylation. Thus glucose is a major fuel for many tissues Carbohydrate Metabolism

29. Apart from glycolysis and TCA cycle, glucose and some of its metabolites also take part in other pathways. Conversion to its storage polymer, glycogen particularly in skeletal liver and muscles – glycogenesis. The hexose monophosphate shunt pathway (HMP shunt pathway) or pentose phosphate pathway, which arises from intermediates of glycolysis is a source of – Reducing equivalents (2H) in the form of NADPH for biosynthesis, e.g. of fatty acids, cholesterol, etc. – Ribose –for the synthesis of nucleotides and nucleic acids. Carbohydrate Metabolism

30. Triose phosphates give rise to glycerol moiety of acyl glycerols (fat). Pyruvate and intermediates of citric acid cycle provide the carbon skeletons for synthesis of amino acids. Acetyl CoA is the building block for long chain fatty acids and cholesterol, which is the precursor for steroids, bile salts and vitamin D. Gluconeogenesis is the process of production of glucose from non-carbohydrate precursors e.g. lactate, amino acids. Carbohydrate Metabolism

31. Summary of Glucose Metabolism