Citric acid cycle. Tomáš Kučera.

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itric acid cycle Tomáš Kučera tomas.kucera@lfmotol.

1 itric acid cycle Tomáš Kučera Department of Medical hemistry and linical Biochemistry 2nd Faculty of Medicine, harles University in Prague and Motol University Hospital 2017

2 Energy metabolism scheme amino acids fatty acids β-oxidation sugars glycolysis pyruvate alternative pathways NADH NAD + NADH NAD + fermentative NAD + regeneration lactate ethanol propionate butyrate butanol formate H2 O2 acetate 2,3-butandiol succinate oxidative decarboxylation citric acid cycle Ac~S oa alvin cycle O 2 NADH NAD + NADPH NADP + ADP respiratory chain O 2 photosynthetic electron transport chain hν ADP ATP oxidative phosphorylation H 2 O photophosphorylation ATP

3 The cycle overview NADH FADH NADH O 2 location mitochondrial matrix the inner mitochondrial membrane (SDH) GTP NADH 4 O 2 zdroj stoichiometry 3 NAD + + FAD + GDP + P + acetyl-soa 3 NADH + 3 H + + FADH 2 + GTP + H-SoA + 2 O 2

4 The cycle overview Importance center of metabolism the smallest building units the lowest level anabolism and catabolism crossing point degradation and synthesis metabolism of sugars, fats, amino acids, porphyrins source of energy in respiratory metabolism

5 Input Ac-oA origin of the acetyl from fats from amino acids from glycolysis Voet, D., Voet, J. G.: Biochemistry, John Wiley & Sons, Inc., 2011 (4th edition)

6 Pyruvate the glycolysis end-product O H 3 OOH important node point of metabolism gluconeogenesis, lipid and aminoacid synthesis... non-respiratory ( anaerobic ) processing pyruvate + NADH + H + lactate + NAD + pyruvate H 3 HO + O 2 H 3 HO + NADH + H + H 3 OH + NAD + respiratory ( aerobic ) processing oxidative decarboxylation acetylcoenzyme A

7 Oxidative decarboxylation of pyruvate multienzyme complex pyruvate dehydrogenase dihydrolipoyl acetyltransferase (transacetylase) dihydrolipoyl dehydrogenase advantages of a multienzyme complex little diffusion limitation minimal side reaction extent coordinated regulation coenzymes thiamin diphosphate lipoamide FAD NAD oa

8 Oxidative decarboxylation of pyruvate Voet, D., Voet, J. G.: Biochemistry, John Wiley & Sons, Inc., 2011 (4th edition) Voet, D., Voet, J. G.: Biochemistry, John Wiley & Sons, Inc., 2011 (4th edition)

9 Lipoic acid Voet, D., Voet, J. G.: Biochemistry, John Wiley & Sons, Inc., 2011 (4th edition)

10 Pyr ox. decarboxylation regulation Voet, D., Voet, J. G.: Biochemistry, John Wiley & Sons, Inc., 2011 (4th edition)

11 The cycle O pyruvate H 3 FADH 2 FAD H 2O ¹ 2 H GTP H ¹ 2 fumarate ¹ 2 ¹ 2 succinate GDP + P i HO ¹ 2 ¹ 2 L-malate H 5. fumarase 6. succinate dehydrogenase NAD + NADH +H + NADH +H + 5. succinyl-oa synthetase oash O S oa succinyl-oa * O 2 acetyl-oa oash + NAD + O 2 + NADH H 3 O oa H 2O O oash * oxaloacetate 6. malate dehydrogenase NAD + oash O * α-ketoglutarate pyruvate dehydrogenase 1. citrate synthase itric acid cycle 4. α-ketoglutarate dehydrogenase O 2 HO S 3. isocitrate dehydrogenase * citrate H 2. aconitase * O oxalosuccinate H 2O HO H * 2. aconitase 3. isocitrate dehydrogenase H NADH +H + cis-aconitate * H isocitrate NAD + H 2O Redrawn after Voet, D., Voet, J. G.: Biochemistry, John Wiley & Sons, Inc., 2011 (4th edition)

12 Glyoxylate cycle Adapted from Voet, D., Voet, J. G.: Biochemistry, John Wiley & Sons, Inc., 2011 (4th edition)

13 TA cycle regulation pyruvate a 2+ acetyl-oa oxalacetate malate citrate fumarate NADH isocitrate succinate GTP succinyl-oa ATP α-ketoglutarate a 2+ a 2+, ADP Redrawn after Voet, D., Voet, J. G.: Biochemistry, John Wiley & Sons, Inc., 2011 (4th edition)

14 TA cycle the core of metabolism Redrawn from Voet, D., Voet, J. G.: Biochemistry, John Wiley & Sons, Inc., 2011 (4th edition)

15 Reverse TA cycle Voet, D., Voet, J. G.: Biochemistry, John Wiley & Sons, Inc., 2011 (4th edition)

16 Anaplerotic reactions glutamate dehydrogenase l-glutamate + H 2 O + NAD(P) + 2-oxoglutarate + NH 3 + NAD(P)H + H + pyruvate carboxylase pyruvate + HO 3 + ATP oxaloacetate + ADP + P + H + aspartate transaminase l-aspartate + 2-oxoglutarate oxaloacetate + l-glutamate purine nucleotide cycle

17 The End konec the end Thank you for your attention!

18 pyruvate H 3 O oash + NAD + pyruvate dehydrogenase O 2 + NADH acetyl-oa H 3 O S oa H 2 O O oash * xaloacetate 1. citrate synthase HO rogenase * citrate 2. aconitase H 2 O H

19 O oash - etate 1. citrate synthase HO se * citrate 2. aconitase H 2 O H * itric acid cycle cis-aconitate H 2 O 2. aconitase edition)

20 citrate 2. aconitase H * itric acid cycle 2. aconitase cis-aconitate H 2 O HO 3. isocitrate dehydrogenase H * H isocitrate + n Wiley & Sons, Inc., 2011 (4th edition)

21 etoglutarate hydrogenase AD + oash O * α-ketoglutarate 3. isocitrate dehydrogenase O 2 H * O HO 3. isocitrate dehydrogenase oxalosuccinate H * NADH +H + H isocitrate NAD + Redrawn after Voet, D., Voet, J. G.: Biochemistry, John Wiley & Sons, Inc., 2011 (4th edition)

22 FAD 6. succinate dehydrogenase ¹ 2 ¹ 2 succinate 5. succinyl-oa synthetase oash GTP 4. α-ketoglutarate dehydrogenase GDP + P i O S oa succinyl-oa NADH +H + * O 2 NAD + oash O * 3. isocitr dehyd α-ketoglutarate O

23 H 2 O ¹ 2 ¹ 2 L-malate 5. fumarase FADH 2 FAD H H ¹ 2 fumarate 6. succinate dehydrogenase ¹ 2 itric acid cycle ¹ 2 succinate 5. succinyl-oa synthetase oash

24 H 2 O ¹ 2 H HO ¹ 2 H ¹ 2 L-malate 5. fumarase NAD + NADH +H + O * oxaloacetate 6. malate dehydrogenase H 2 O oash 1. citrate synthase FADH 2 H ¹ 2 fumarate 6. succinate dehydrogenase itric acid cycle

25 2 4 6 NADH NADH O 2 FADH 2 5 GTP NADH 4 O 2

31 pyruvate a 2+ acetyl-oa oxalacetate malate citrate fumarate NADH isocitrate a 2+, ADP succinate GTP ATP succinyl-oa α-ketoglutarate a 2+

Citric Acid Cycle: Central Role in Catabolism. Entry of Pyruvate into the TCA cycle

Citric Acid Cycle: Central Role in Catabolism Stage II of catabolism involves the conversion of carbohydrates, fats and aminoacids into acetylcoa In aerobic organisms, citric acid cycle makes up the final