Introduction to Metabolism

1. Introduction to Metabolism • A hummingbird has a rapid rate of metabolism, but its basic metabolic reactions are the same as those in many diverse organisms

2. Autotrophs – use CO2 as sole carbon source (plants, photosynthetic bacteria, etc.) • Heterotrophs-obtain carbon from their environment • Constant cycling of material between autotrophs and heterotrophs Chapter 10

3. Chapter 10

4. Metabolism Is the Sum of Cellular Reactions • Metabolism - the entire network of chemicalreactions carried out by living cells • Metabolites - small molecule intermediates in the degradation and synthesis of polymers • Catabolic reactions - degrademolecules to create smaller molecules and energy • Anabolic reactions - synthesize molecules for cell maintenance, growth and reproduction

5. Anabolism and catabolism

6. Chapter 10

7. Metabolic Reactions • Metabolism includes allenzymecatalyzed reactions • The metabolism of the four major groups of biomolecules will be considered: Carbohydrates Lipids Amino Acids Nucleotides

8. Organization of Metabolic Reactions • Occur via pathways – series of organized reaction steps • Compartmentalized – certain reactions occur in particular cells, organelles or other specific sites • Pathways are regulated – controlled • to keep anabolism and catabolism reactions separate (some use the same enzymes) • Timing to produce products only when necessary • At least one step in a pathway needs to be irreversible (exergonic, -G) Chapter 10

9. Types of pathways • Individual reaction series • Linear (can branch out) • Cyclic • Spiral • Connecting pathways • Converging (metabolic) • Diverging (anabolic) Chapter 10

10. Forms of metabolic pathways • Linear (b) Cyclic • or branched

11. (c) Spiral pathway (fatty acid biosynthesis)

12. Chapter 10

13. Metabolism Proceeds by Discrete Steps • Multiple-steppathways permit control of energy input and output • Catabolic multi-step pathways provide energy in smallerstepwiseamounts) • Each enzyme in a multi-step pathway usually catalyzes only one single step in the pathway • Controlpoints occur in multistep pathways

14. Single-step vs multi-step pathways • A multistep enzyme pathway releases energy in smaller amounts that can be used by the cell

15. Metabolic Pathways Are Regulated • Regulation permits response to changing conditions • Common ways to regulate • (1) Supply of substrates(concentration) (2) Removal of products (3) Pathway enzyme activities • Allosteric regulation • Covalent modification

16. Feedback inhibition • Product of a pathway controls the rate of its own synthesis by inhibiting an early step (usually the first “committed” step (unique to the pathway)

17. Feed-forward activation • Metabolite early in the pathway activates an enzyme further down the pathway

18. Covalent modification for enzyme regulation • Interconvertible enzyme activity can be rapidly and reversibly altered by covalentmodification • Protein kinases phosphorylate enzymes (+ ATP) • Protein phosphatases remove phosphoryl groups • The initial signal may be amplified by the “cascade” nature of this signaling

19. Reaction Types in Pathways • Oxidation-Reduction (Redox) • Making or breaking C-C bonds • Internal rearrangements, isomerizations or eliminations • Group transfers • Free radical reactions Chapter 10

20. Redox reactions • Oxidation – loss of electrons, gain of oxygen, loss of hydrogen • Hydrogenases • Oxidases • Note the different oxidation states of carbon Chapter 10

21. Chapter 10

22. Chapter 10

23. Carbon-Carbon Bonds • Bond cleavage • Homolytic (1 electron for each atom) • Heterolytic (both electrons to one atom) • Recall • Nucleophiles (attracted to + charges) • Electrophiles (attracted to – charges) Chapter 10

24. Chapter 10

25. Common Reaction Types • Many use the carbonyl group C=O • + on Carbon; - on Oxygen • Reactive group in • Aldol condensations • Claisen condensations • Decarboxylations Chapter 10

26. Chapter 10

27. Internal Reactions • Rearrangements, isomerizations, eliminations • Groups • Bonds • Atoms Chapter 10

28. Chapter 10

29. Chapter 10

30. Group Transfers • There are many groups to transfer • Acyl • Glycosyl • Phosphoryl • Phosphate = Pi • Pyrophosphate = PPi Chapter 10

31. Chapter 10

32. Free Radicals • Unpaired electrons • More common than previously thought Chapter 10

33. 10.3 Major Pathways in Cells • Metabolic fuels • Three major nutrients consumed by mammals: (1) Carbohydrates - provide energy(2) Proteins - provide amino acids for protein synthesis and some energy(3) Fats - triacylglycerols provide energy and also lipids for membrane synthesis

34. Fig 10.5 • Overview of catabolic pathways

35. Catabolism produces compounds for energy utilization • Three types of compounds are produced that mediate the release of energy • (1) Acetyl CoA • (2) Nucleoside triphosphates (e.g. ATP) • (3) Reduced coenzymes (NADH, FADH2, QH2)

36. Electrons of reduced coenzymes flow toward O2 • This produces a protonflow and a transmembranepotential • Oxidative phosphorylationis the process by which the potential is coupled to the reaction: ADP + Pi ATP Reducing Power

37. 10.4 Compartmentation and Interorgan Metabolism • Compartmentation of metabolic processes permits: • - separate pools of metabolites within a cell • - simultaneous operation of opposing metabolic paths • - high local concentrations of metabolites • - coordinated regulation of enzymes • Example: fatty acid synthesis enzymes (cytosol), fatty acid breakdown enzymes (mitochondria)

38. Fig. 10.6 Compartmentation of metabolic processes

39. 10.5 Thermodynamics and Metabolism A. Free-Energy Change • Free-energy change(DG) is a measure of the chemicalenergyavailablefromareaction • DG = Gproducts - Greactants • DH = change in enthalpy • DS = change in entropy

40. Both entropy and enthalpy contribute to DG • DG = DH - TDS • (T = degrees Kelvin) • -DG = a spontaneous reaction in the direction written • +DG= the reaction is not spontaneous • DG= 0 the reaction is at equilibrium Relationship between energy and entropy

41. The Standard State (DGo) Conditions • Reaction free-energy depends upon conditions • Standard state(DGo)- defined reference conditions • Standard Temperature = 298K (25oC) • Standard Pressure = 1 atmosphere • Standard Solute Concentration = 1.0M • Biological standard state =DGo’ • Standard H+ concentration = 10-7 (pH = 7.0) rather than 1.0M (pH = 1.0)

42. For the reaction: A + B C + D B. Equilibrium Constants and Standard Free-Energy Change DGreaction = DGo’reaction + RT ln([C][D]/[A][B]) • At equilibrium: Keq = [C][D]/[A][B] and DGreaction = 0, so that: DGo’reaction = -RT ln Keq

43. C. Actual Free-Energy Change Determines Spontaneity of Cellular Reactions • When a reaction is not at equilibrium, the actual free energy change (DG) depends upon the ratio of products to substrates • Q = the mass action ratio DG = DGo’ + RT ln Q Where Q = [C]’[D]’ / [A]’[B]’

44. 10.6 The Free Energy of ATP • Energy from oxidation of metabolic fuels is largely recovered in the form of ATP

45. Table 10.1

46. Fig 10.7 • Hydrolysis of ATP

47. Fig 10.8 Complexes between ATP and Mg2+

48. ATP is an “energy-rich” compound • A large amount of energy is released in the hydrolysis of the phosphoanhydridebonds of ATP (and UTP, GTP, CTP) • All nucleoside phosphates have nearly equal standard free energies of hydrolysis

49. Energy of phosphoanhydrides (1) Electrostaticrepulsion among negatively charged oxygens of phosphoanhydrides of ATP (2) Solvationofproducts (ADP and Pi) or (AMP and PPi) is better than solvation of reactant ATP (3) Productsaremorestablethanreactants There are more delocalized electrons on ADP, Pi or AMP, PPi than on ATP

50. 10.7 The Metabolic Roles of ATP • Energy-rich compounds can drive biosynthetic reactions • Reactions can be linked by a common energized intermediate (B-X) below • A-X + B A + B-X • B-X + C B + C-X