A SURVEY OF METABOLISM. HLeeYu Jsuico Junsay Department of Chemistry School of Science and Engineering Ateneo de Manila University

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1 A SURVEY F METABLISM HLeeYu Jsuico Junsay Department of Chemistry School of Science and Engineering Ateneo de Manila University 1

2 Why do living organisms need energy? 1. Energy for moeon kineec energy 2. Maintain homeostasis steady state, poteneal energy 3. Build up the organism s components from available nutrients chemical energy 4. Removes waste chemical and kineec energy 5. Responds to environmental changes chemical energy 6. Remove and regenerate damaged parts chemical energy 2

3 The study of metabolism allows us to understand how all the cell s process are done! In some way, it is also a study of how energy is transformed by the organism from one form to another! 3

4 Above and beyond all characterisecs, it is metabolism that provides the best working definieon of life. It is metabolism and not replicaeon that provides the best working definieon of life. EvoluEonary biologists would say that we exist in order to reproduce but we are not, even the most amorous of use, trying to reproduce all the Eme. Yet, if we stop metabolizing, even for a minute or two, we are done for.» Phillip Ball in Stories of the Invisible: A Guided Tour of Molecules, xford University Press,

5 METABLISM 5

6 rganisms can be divided to many metabolismbased classes. Autotroph vs. Heterotroph 6

7 rganisms can be divided to many metabolismbased classes. Aerobes vs. Anaerobes 7

8 The pathway by which molecules degrade and synthesize compounds is called the metabolic pathway A study of energy transfer from food to biological molecules 8

9 Enzyme complexes provide the machinery for metabolism 9

10 Energy is carried from one form to another by chemical compounds METABLITES. 10

11 Metabolism is carried out in 3 stages: 1. DegradaEon/ Synthesis of complex metabolites 2. TransformaEon of simple metabolites 3. Energy pay off 11

12 rganisms maintain non equilibrium condieons between the self and the non self: steady state. Surroundings System Equilibrium Steady State NT at equilibrium McKee and McKee (1999) Biochemistry: An IntroducEon. Figure 4.2, p. 64. And when we talk about energy and equilibrium, we usually look at thermodynamics. 12

13 BILGICAL THERMDYNAMICS 13

14 Thermodyamics considers the energelcs of a reaclon. FIRST LAW: You can t win. Energy cannot be created or destroyed. It is only transformed into other forms ΔE system = Δ E surrounding 14

15 Thermodyamics considers the energelcs of a reaclon. SECND LAW: You always lose. The total entropy of the universe (entropy of system + surrounding) increases in a spontaneous reaceon ΔS total = ΔS system + ΔS surroundings > 0 15

16 Thermodyamics considers the energelcs of a reaclon. THIRD LAW: You will never get there/ PerfecLon is boring The entropy, S, of a pure, perfectly crystalline solid at absolute zero is 0. 16

17 Gibbs free energy, ΔG, is the maximum useful work that can be produced by a chemical reaceon. ΔG = ΔH TΔS ΔG < 0 The reaceon is spontaneous in the forward direceon. ΔG > 0 The reaceon is non spontaneous as wrinen. The reaceon is spontaneous in the reverse direceon. ΔG = 0 The reaceon is at equilibrium. 17

18 Thermodyamics considers the energelcs of a reaclon. ΔG is the maximum useful work that can be produced by a chemical reaclon. 18

19 EnergeEcally unfavorable reaceons are coupled to favorable ones to drive them forward. (this is how organisms win!) 19

20 EnergeEcally unfavorable reaceons are coupled to favorable ones to drive them forward. ΔG = + 17 kj/mol ΔG = 30 kj/mol 20

21 Coupled reaceons passes through a different mechanism whose overall yield give ΔG<0 21

22 CHEMICAL STRATEGIES 22

23 rganisms use common chemical strategies in energy management. 23

24 Phosphoryl transfer reaceons yield very negaeve ΔG making them ideal for coupling with other reaceons 24

25 Phosphoryl transfer reaceons yield very negaeve ΔG making them ideal for coupling with other reaceons 25

26 ATP has intermediate phosphoryl transfer poteneal. Less reaclve than PEP, kinelcally stable. 26

27 ATP has intermediate phosphoryl transfer poteneal. 27

28 Why do we need an intermediate metabolite as energy carrier? 28

29 Phophoryl transfer molecules are used up in the cells depending on certain conditions 29

30 Phophoryl transfer molecules are used up in the cells depending on certain conditions 30

31 xidaeon reduceon reaceons need redox partners. 31

32 xidaeon reduceon reaceons need redox partners. 32

33 These redox partners are usually electron carriers.. To other molecules or to respiratory enzymes 33

34 CASE STUDY: GLYCLYSIS AND THE FATES F PYRUVATE 34

35 Glycolysis and the citric acid cycle are at the center of the metabolic processes in living organisms 35

36 Glucose metabolism involves both energy producing (catabolic, orange) and energy consuming (anabolic, green) processes 36

37 WHY GLUCSE?! The only fuel the brain uses in nonstarvaeon condieons The only fuel red blood cells can use WHY? EvoluEonary: probably available for primieve systems (from formaldehyde) Low tendency to glycosylate proteins, strong tendency to exist in ring form (recall: all equatorial!) 37

38 Glycolysis turns glucose to pyruvate which then can be uelized in fermentaeon or thru complete oxidaeon. 38

39 Glycolysis occurs in three major stages: 1. INVESTMENT: Glucose fructose 1,6 biphosphate 2. MULTIPLIER: Fructose 1,6 biphosphate glyceraldehyde 3 phosphate 3. PAYBACK: Glyceraldehyde 3 phosphate Pyruvate 39

40 STEP 1: PhosphorylaEon of glucose using hexokinase (or glucokinase) to glucose 6 phosphate (G6P) H -2 3 P H hexokinase H H H ATP ADP H H Glucose H H Glucose-6-phosphate This step is a priming step uses ATP to get more ATP later, Very negaeve ΔG Done to keep glucose in the cytoplasm 40

41 STEP 1: PhosphorylaEon of glucose using hexokinase (or glucokinase) to glucose 6 phosphate (G6P) This step is a priming step uses ATP to get more ATP later, Very negaeve ΔG Done to keep glucose in the cytoplasm 41

42 STEP 2: IsomerizaEon of G6P to fructose 6 phosphate -2 3 P H -2 3 P phosphogluycoisomerase H H H H H Glucose-6-phosphate 3 rd step will be easier on a primary H, rather than a hemiacetal Readies the compound for later cleavage between C3 C4 H H Fructose-6-phosphate 42

43 STEP 2: IsomerizaEon of G6P to fructose 6 phosphate 3 rd step will be easier on a primary H, rather than a hemiacetal Readies the compound for later cleavage between C3 C4 43

44 STEP 3: PhosphorylaEon of F6P to fructose 1,6 bisphosphate (using Phosphofructokinase, PFK) -2 3 P H -2 3 P P 3-2 H phosphofructokinase H H H Fructose-6-phosphate ATP ADP H H Fructose-1,6-bisphosphate This is another priming step Uses ATP to get more ATP later, Very negaeve ΔG This is the commibed step: F 1,6 BP is very reaceve! PFK, Inhibited by lots of ATP. (if you don t need energy, your step will not occur) 44

45 Recall STAGE 1: INVESTMENT 45

46 STEP 4: Cleaving the 6C molecule to two 3C molecules -2 3 P P H H Fructose-1,6-bisphosphate Aldolase Done by aldolase (a reverse aldol condensaeon reaceon) H 2 C C CH 2 H P - Dihydroxyacetone phosphate(dhap) HC HC CH 2 H P - Glyceraldehyde-3- phosphate (G-3-P) - 46

47 STEP 4: Cleaving the 6C molecule to two 3C molecules Done by aldolase (a reverse aldol condensaeon reaceon) 47

48 STEP 5: Converts DHAP to G 3 P HC H 2 C C P - - Triose-phosphate isomerase HC CH 2 H P - CH 2 H Dihydroxyacetone phosphate(dhap) - Glyceraldehyde-3-phosphate (G-3-P) Uses Triose phosphate isomerase This reaceon yields an overall two (2) G 3 P per molecule of glucose 48

49 STEP 5: Converts DHAP to G 3 P Uses Triose phosphate isomerase This reaceon yields an overall two (2) G 3 P per molecule of glucose 49

50 Recall STAGE 2: MULTIPLIER 50

51 CHECKLIST: We ve USED UP 2 ATP molecules to process 1 glucose molecule We are les with 2 G3P now Time for energy payback, thus STAGE 3! Recall that stage 3 happens in parallel to the two G3P molecules 51

52 STEP 6: G 3 P is oxidized to 1,3 bisphosphate glycerate (1,3 BPG) H P 3-2 C C HC H + HP 4-2 G-3-P dehydrogenase HC H + H + CH 2 P - CH 2 P - - NAD + NADH - Glyceraldehyde-3-phosphate (G-3-P) 1,3-bisphosphate glycerate (1,3-BPG) Yields NADH, an electron carrier! Yields a highly reaceve 1,3 BPG, a phosphoryl carrier! 52

53 STEP 7: 1,3 BPG is transformed to 3 phosphoglycerate (3 PG) P 3-2 H C phophoglycerate kinase C HC H HC H CH 2 P - ADP ATP CH 2 P ,3-bisphosphate glycerate (1,3-BPG) 3-phosphoglycerate (3-PG) Yields ATP payback Eme! (remember for every step here, two are actually yielded due to the two G 3 P molecules that we made earlier!) 53

54 STEP 8: 3 PG is converted to 2 PG H H C phophoglycerate mutase C HC H HC P - CH 2 P - CH 2 H phosphoglycerate (3-PG) 2-phosphoglycerate (2-PG) Places phosphate from C3 to C2.. Readies the molecule to make Phosphoenol pyruvate, another highly reaceve compound! 54

55 STEP 9: 2 PG is re arranged to phosphoenol pyruvate (PEP) H H C enolase C HC P - C P - CH 2 H - H 2 CH 2-2-phosphoglycerate (2-PG) Phosphoenol pyruvate (PEP) Enolase creates an enol like funceonal group. 55

56 STEP 9: PEP is converted to Pyruvate H C pyruvate kinase H C keto-enol tautomerization H C C CH 2 P - - ADP + H + ATP H 2 C C H H 3 C C Phosphoenol pyruvate (PEP) pyruvate Yields ATP another payback step! 56

57 Recall STAGE 3: PAYBACK 57

58 CHECKLIST: Made 2 NADH (one from each G 3 P) Made 4 ATP (two from each G 3 P) VERALL Mass balance: Glucose + 2 P i + 2ADP + 2 NAD Pyruvate + NADH + 2 ATP + 2H + + 2H 2

59 NADH has two possible fates: fermentaeon or respiraeon FermentaLon: In the absence of 2, NADH is used as a chemical reductant of pyruvate to make lactate 59

60 NADH has two possible fates: fermentaeon or respiraeon RespiraLon: In the presence of 2, NADH is used as a electron carrier to harness energy in the mitochondria. 60

61 Pyruvate has three possible fates: lactate fermentaeon, alcohol fermentaeon and complete oxidaeon Lactate FermentaLon: In the absence or short supply of 2, pyruvate is converted to lactate (via lactate dehydrogenase). Reverse is done by the same enzyme. 61

62 Pyruvate has three possible fates: lactate fermentaeon, alcohol fermentaeon and complete oxidaeon Lactate FermentaLon: In the absence or short supply of 2, pyruvate is converted to lactate (via lactate dehydrogenase). Reverse is done by the same enzyme. 62

63 Pyruvate has three possible fates: lactate fermentaeon, alcohol fermentaeon and complete oxidaeon H 3 C H alcohol decarboxylase C 2 H 3 C H alcohol dehydrogenase NADH + H + NAD + H 3 C H C H H pyruvate acetaldehyde ethanol Ethanol FermentaLon: In anaerobic bacteria/yeast, pyruvate is decarboxylated then reduced to ethanol 63

64 Pyruvate has three possible fates: lactate fermentaeon, alcohol fermentaeon and complete oxidaeon HSCoA NAD+ NADH + H + C 2 H SCoA H 3 C pyruvate dehydrogenase complex (E 1 + E 2 + E 3 ) H 3 C pyruvate Acetyl-CoA RespiraLon: In the presence of 2, pyruvate is converted to Acetyl CoA which will be fed onto the tricarboxylic acid cycle. 64

65 The energeecs of glycolysis reveals three important things: 1. Most of the process is not energy intensive and are thus reversible 2. There are three irreversible steps: 1, 3 and These steps are possibly where regulaeon can happen 65

66 66

67 67

68 ther monosaccharides can also enter glycolysis. 68

69 69

70 The synthesis of glucose from pyruvate, lactate, amino acids or other metabolites, is called gluconeogenesis. ccurs mainly in liver and kidneys Not the mere reversal of glycolysis for 2 reasons: EnergeEcs must change to make gluconeogenesis favorable (delta G of glycolysis = 74 kj/mol Reciprocal regulaeon must turn one on and the other off this requires something new! 70

71 The synthesis of glucose from pyruvate, lactate, amino acids or other metabolites, is called gluconeogenesis. Seven steps of glycolysis are retained: Steps 2 and 4 9 Three steps are replaced: Steps 1, 3, and 10 (the regulated steps!) The new reaceons provide for a spontaneous pathway (ΔG negaeve in the direceon of sugar synthesis), and they provide new mechanisms of regulaeon Make sure you know the THREE BYPASS STEPS of Gluconeogenesis!!! 71

72 The synthesis of glucose from pyruvate is called gluconeogenesis. ccurs mainly in liver and kidneys Not the mere reversal of glycolysis for 2 reasons: EnergeEcs must change to make gluconeogenesis favorable (delta G of glycolysis = 74 kj/mol Reciprocal regulaeon must turn one on and the other off this requires something new! 72

73 The synthesis of glucose from pyruvate, lactate, amino acids or other metabolites, is called gluconeogenesis. 73

74 The synthesis of glucose from pyruvate is called gluconeogenesis. 74

75 75

76 Aside from (+) and( ) effectors, hormones control gene expression. 76

77 Aside from (+) and( ) effectors, hormones control gene expression. 77

78 CASE STUDY: TRICARBXYLIC ACID CYCLE AND ELECTRN TRANSPRT CHAIN 78

79 Acetyl CoA enters a cycle that converts it to C 2 and lots of electron carriers 79

80 Acetyl CoA enters a cycle that converts it to C 2 and lots of electron carriers 80

81 Acetyl CoA react with xaloacetate and is converted to Citrate. The cycle regenerates the oxaloacete, disposes of the C 2 and yield lots of energy carriers. 81

82 Acetyl CoA react with xaloacetate and is converted to Citrate. The cycle regenerates the oxaloacete, disposes of the C 2 and yield lots of energy carriers. 82

83 Acetyl CoA react with xaloacetate and is converted to Citrate. The cycle regenerates the oxaloacete, disposes of the C 2 and yield lots of energy carriers. 83

84 Acetyl CoA react with xaloacetate and is converted to Citrate. The cycle regenerates the oxaloacete, disposes of the C 2 and yield lots of energy carriers. 84

85 NADH and FADH 2 carries high energy electron which creates a hydrogen poteneal which in turn creates ATP 85

86 NADH and FADH 2 carries high energy electron which creates a hydrogen poteneal which in turn creates ATP. 1 NADH = 3 ATP, 1 FADH 2 = 2 ATP. 86

87 Glycolysis + Pyruvate dehydrogenase + TCA = lots of energy 87

88 CASE STUDY: BETA XIDATIN F FATS 88

89 Fats are degraded by cuung them up into C2 fragments: Acetyl CoA and fed into the TCA. 89

90 Fats are degraded by cuung them up into C2 fragments: Acetyl CoA and fed into the TCA. 90

91 SUMMARY 91

92 Metabolism of nutrients involve Breakdown from biomolecules to simple molecules Simple molecules are converted to feeder molecules Glycolysis, Pyruvate dehydrogenase, B oxidaeon Feeder molecules are fed to a cycle that produces lots of energy carriers TCA NADH + FAH 2 Energy carriers are processed and can release lots of ATP Electron transport Chain THESE PRCESSES ARE TIGHTLY REGULATED 92

93 Above and beyond all characterisecs, it is metabolism that provides the best working definieon of life. It is metabolism and not replicaeon that provides the best working definieon of life. EvoluEonary biologists would say that we exist in order to reproduce but we are not, even the most amorous of use, trying to reproduce all the Eme. Yet, if we stop metabolizing, even for a minute or two, we are done for.» Phillip Ball in Stories of the Invisible: A Guided Tour of Molecules, xford University Press,

GLYCOLYSIS Generation of ATP from Metabolic Fuels

GLYCOLYSIS Generation of ATP from Metabolic Fuels - Catabolic process degradative pathway - Energy stored in sugars (carbohydrates) released to perform biological work - Transforms GLUCOSE to PYRUVATE