Lecture'22:'April'30,'2013 Ch.%29:%Metabolism,%catabolism,%anabolism Metabolic%energy%&%ATP%Coupling Glycolysis%and%the%Link%ReacDon

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1 CM'224' 'rganic'chemistry'ii pring'2013,'des'laines' 'rof.'chad'landrie Gº' = Lecture'22:'April'30,'2013 Ch.%29:%Metabolism,%catabolism,%anabolism Metabolic%energy%&%AT%Coupling Glycolysis%and%the%Link%ReacDon

2 Metabolic*athways Metabolism: Chemical reactions of biomolecules in living systems Anabolic: athways that synthesize larger molecules from smaller; typically use energy in the form of AT (aka biosynthesis) Catabolic: athways that degrade larger molecules into smaller; often used to produce energy in the form of AT Fatty-acid Biosynthesis Glycolysis Link Reaction 3 C CoA acetyl CoA biotin-c 2 CoA malonyl CoA fatty-acids glycolysis AD + AD CoA link reaction CoA glucose pryuvate acetyl CoA Terpenoid & teroid Biosynthesis 3 C 3 C CoA CoA acetyl CoA mevalonate isopentenyl pyrophospate (I) Kreb s Cycle CoA acetyl CoA C 2 + AD + AT rganic Chemistry II (CM 224) lide 2

3 Metabolic*athways Metabolism: Chemical reactions of biomolecules in living systems These are the only three metabolic pathways we are going to cover in this chapter. We will not cover: Fatty-acid catabolism (29.2, 29.3) Gluconeogenesis, anabolic (29.8) We have already covered: Fatty-acid biosynthesis (29.4) rotein catabolism (29.9) Catabolic: athways that degrade larger molecules into smaller; often used to produce energy in the form of AT Glycolysis glucose Kreb s Cycle CoA acetyl CoA glycolysis Link Reaction pryuvate AD + AD CoA link reaction CoA acetyl CoA C 2 + AD + AT rganic Chemistry II (CM 224) lide 3

4 Krebs *Three*tages*of*Energy*Extrac:on*(Aerobic) Fats olysaccharides roteins fatty acids and glycerol glucose and other sugars amino acids tage I Glycolysis tage II 3 C CoA acetyl CoA CoA 2 AT AD + i xidative hosphorylation e (AD) Citric Acid Cycle tage III rganic Chemistry II (CM 224) lide 4

5 xida:ve*hosphoryla:on*&*electron*transport*chain AD is carrier of electrons in bonds of glucose (bond energy) series of cytochrome enzymes accept the electrons from AD and FAD2 and transport to ultimate acceptor, 2 produce + along the way = proton gradient develops 2 R AD oxidation 2 R AD e + + this gradient is a form of energy and activates AT synthase as protons move through AT synthase AT stores energy for later rganic Chemistry II (CM 224) lide 5

6 Key*layers 2 adenosine triphosphate (AT) Enz biotin-c 2 R AD: R = ; AD: R = nicotinamide adenine dinucleotide- rganic Chemistry II (CM 224) lide 6

7 Key*layers -CoA is an acyl carrier cofactor thioester bond is more easily hydrolyzed than an ester; ideal for biological systems rganic Chemistry II (CM 224) lide 7

8 ew*key*layers 2 C 3 4 Enz lipoamide thiamine pyrophosphate (T) Used in the link reaction to transfer the acyl group of pyruvate (from glycolysis) to -CoA before entering Krebs rganic Chemistry II (CM 224) lide 8

9 Adenosine*Triphosphate*(AT) 2 Adenine Ribose Triphosphate Energy currency for metabolic processes bonds are high potential energy bonds phophorylation (cleavage of those bonds) is exergonic (spontaneous) process this process is coupled to other endergonic (non spontaneous) processes to shift the equilibrium to the right rganic Chemistry II (CM 224) lide 9

10 Mechanism*of*hosphoryla:on Mg 2+ Adenosine Adenosine kinase Mg 2+ + :uc uc kinases are enzymes that catalyze phosphorylation hexokinases phosphorylate C6 sugars all kinases require magnesium or manganese (2+) for activity divalent metal forms complex with AT rganic Chemistry II (CM 224) lide 10

11 Coupled*Reac:ons*and*ess s*law A B + C ΔG ' = +5 kcal/mol B D ΔG ' = 8 kcal/mol A C + D ΔG ' = 3 kcal/mol Free Energy (Gº ) B + C 5 A 8 3 C + D reaction coordinate ess s Law (1st Law of Thermodynamics): The total enthalpy change of a processes is independent of the path (state function) A nonspontaneous reaction (endergonic; + G) can be coupled to a spontaneous reaction (exergonic; G) so the overall process is spontaneous. rganic Chemistry II (CM 224) lide 11

12 AT*ydrolysis*Can*hiJ*Equilibrium*by*10 8 Uncoupled A B ΔG ' = +4 kcal/mol K = [B] eq [A] = G RT 10 K = [B] 10 (4) eq [A] = 1.36 K = [B] eq [A] = rganic Chemistry II (CM 224) lide 12

13 AT*ydrolysis*Can*hiJ*Equilibrium*by*10 8 Coupled A B ΔG ' = +4 kcal/mol AT + 2 AD + i + + ΔG ' = 7.3 kcal/mol A + AT + 2 B + AD + i + + ΔG ' = 3.3 kcal/mol K eq = [B] [A] [AD][i] [AT] K eq = [B] [A] [AD][i] [AT] K eq = [B] [A] [AD][i] [AT] = 10 G RT = 10 ( 3.3) 1.36 = [B] [A] = [B] [A] [B] [A] K eq [AT] [AD][i] = ( 2.67 )( ) = cellular AT:AD rganic Chemistry II (CM 224) lide 13

14 AT*ydrolysis*Can*hiJ*Equilibrium*by*10 8 Coupled A B ΔG ' = +4 kcal/mol AT + 2 AD + i + + ΔG ' = 7.3 kcal/mol A + AT + 2 B + AD + i + + ΔG ' = 3.3 kcal/mol Uncoupled A B ΔG ' = +4 kcal/mol [B] [A] coupled = [B] [A] uncoupled ~ rganic Chemistry II (CM 224) lide 14

15 tructural*basis*for*hosphoryl*transfer*oten:al*of*at Gº' = vs. C 2 C 2 2 Gº' = -2.2 C 2 C 2 + glycerol 3-phosphate glycerol rganic Chemistry II (CM 224) lide 15

16 tructural*basis*for*hosphoryl*transfer*oten:al*of*at Gº' = electrostatic repulsion in AT high negative charge increases potential energy of AT one additional resonance contributor for orthophosphate (4 2 ) and AD compared to AT alone board work rganic Chemistry II (CM 224) lide 16

17 ther*hosphoryla:ng*agents 2 C phosphoenolpyruvate C 3 acetyl phosphate C 2 2 creatine phosphate C pyruvate + i 3 C acetate + i 2 2 C 2 creatine + i rganic Chemistry II (CM 224) lide 17

18 ther*hosphoryla:ng*agents 2 C phosphoenolpyruvate C 3 acetyl phosphate C 2 2 creatine phosphate Compound Gº (kcal/mol) phosphoenolpyruvate C pyruvate + 2 i 3 C acetate + 2 i 2 2 C creatine i acetyl phosphate creatine phosphate AT (to AD) -7.3 muscle stores of AT can sustain contraction for less than a second creatine phosphate reservoirs in muscle produce AT (AD + ~ AT) glucose 1-phosphate -5.0 glucose 6-phosphate -3.3 glycerol 3-phosphate -2.2 rganic Chemistry II (CM 224) lide 18

19 Kine:c*tability Although phosphoryl transfer is exergonic, AT is kinetically stable: there is a large energy barrier (activation energy; Ea). hosphorylation requires catalysis by an enzyme (Ea 2 ), which only lowers the Ea2 Free Energy (Gº ) AT + 2 Gº = -7.3 kcal/mol Ea 1 Ea 2 AD + i + + reaction coordinate rganic Chemistry II (CM 224) lide 19

20 CM'224' 'rganic'chemistry'ii pring'2013,'des'laines' 'rof.'chad'landrie Glycolysis ecdon%ubdtle

21 verview*of*glycolysis C 2 1. Glucose Cleavage 2 C glyceraldehyde-3-phosphate (G3) (C 3 ) 2. Aldehyde xidation 2 3 2_ C 2 3-phosphoglycerate (C 3 ) glucose (C 6 ) 3. Dehydration/ hosphorylation 2 pyruvates produced/1 glucose overall nets 2 AT and 1 AD 2 3 C pyruvate (C 3 ) rganic Chemistry II (CM 224) lide 21

22 Glycolysis Board Work: 1. Cleavage of glucose 2. Aldolase mechanism 3. Aldehyde oxidation of G3 4. G3 dehydrogenase mechanism 5. yruvate rganic Chemistry II (CM 224) lide 22

23 CM'224' 'rganic'chemistry'ii pring'2013,'des'laines' 'rof.'chad'landrie Fates'of'yruvate

24 3*Fates*of*yruvate 1. Lactic Acid Fermentation 2. Alcoholic Fermentation lactate C AD + AD pyruvate C 3 + C 2 C 3 acetaldehyde + + AD AD + C 3 ethanol AD + + CoA AD + C 2 3. yruvate Decarboxylation (Link Reaction) CoA C 3 acetyl CoA enters Kreb s cycle rganic Chemistry II (CM 224) lide 24

25 Link*Reac:on C 3 2 thiamine pyrophosphate (T) 4 lipoamide Enz T converts ketone carbonyl from electrophile to nucleophile (umpolung) - bond good electrophile transthioesterification gives acetyl CoA pyruvate (C 3 ) R thiamine pyrophosphate (T) 3 C R -CoA 3 C CoA acetyl CoA (C 2 ) R R C 3 C hydroxyethyl thiamine pyrophosphate R lipoamide AD + AD + + rganic Chemistry II (CM 224) lide 25

26 Review:*Benzoin*Condensa:on Umpolung: apparent reversal of nucleophilicity or electrophilicity of a funcational group. rganic Chemistry II (CM 224) lide 26

27 Review:*Benzoin*Condensa:on Umpolung: apparent reversal of nucleophilicity or electrophilicity of a funcational group. rganic Chemistry II (CM 224) lide 27

28 Review:*Benzoin*Condensa:on thiamine cyanide equivalent rganic Chemistry II (CM 224) lide 28

29 Review:*Benzoin*Condensa:on thiamine cyanide equivalent rganic Chemistry II (CM 224) lide 29

30 Link*Reac:on C 3 2 thiamine pyrophosphate (T) 4 lipoamide Enz T converts ketone carbonyl from electrophile to nucleophile (umpolung) - bond good electrophile transthioesterification gives acetyl CoA pyruvate (C 3 ) R thiamine pyrophosphate (T) 3 C R -CoA 3 C CoA acetyl CoA (C 2 ) R R C 3 C hydroxyethyl thiamine pyrophosphate R lipoamide AD + AD + + rganic Chemistry II (CM 224) lide 30

31 Link*Reac:on Board Work: 1. Deprotonation of T (carbene ylide) 2. Addition to pyruvate 3. Decarboxylation 4. Addition to lipoamide 5. Transthioesterification with -CoA 2 C 3 4 Enz lipoamide thiamine pyrophosphate (T) rganic Chemistry II (CM 224) lide 31

32 CM'224' 'rganic'chemistry'ii pring'2013,'des'laines' 'rof.'chad'landrie ext'lecture.'.'. Ch.%27:%rostaglandins,%Terpenoids%and% teroids.%biosynthedc%pathways. Ch.%28:%Biomolecules:%ucleic%Acids