1. The Citric Acid Cycle

2. The Citric Acid Cycle
Three processes play central role in aerobic metabolism
the citric acid cycle
electron transport
oxidative phosphorylation
Metabolism consists of
catabolism: the oxidative breakdown of nutrients
anabolism: the reductive synthesis of biomolecules
The citric acid cycle is amphibolic; that is, it plays a role in both catabolism and anabolism
It is the central metabolic pathway

3. Mitochondrion The Powerhouse of the Cell

4. The Citric Acid Cycle TCA cycle= Krebs cycle= Citric acid cycle
In Eukaryotes, cycle occurs in the mitochondrial matrix
In Prokaryotes CAC occurs in the cytosol
mitochondrion

5. The Citric Acid Cycle Pyruvate Acetyl -CoA GDP GTP F A D H N C O2 N + C O
Citric
acid
cycle
(8 steps)
Coenzyme A
CO2

6. Summary Of Reactions Of CAC Can I Keep Selling Sex For Money Officer

8. Pyruvate to Acetyl-CoA
Oxidative decarboxylation reaction
Occurs in the mitochondria
this reaction requires NAD+, FAD, Mg2+, thiamine pyrophosphate, coenzyme A, and lipoic acid
G°’ = kJ•mol-1

9. Structure of the pyruvate dehydrogenase complex
E1, pyruvate dehydrogenase (yellow) (; E2, dihydrolipoyl transacetylase;(green) and E3,dihydrolipoyl dehydrogenase (red). The lipoyl domain of E2 (blue)

11. Congenital Lactic Acidosis
Absence of pyruvate decarboxylase activity in man ( first enzyme ).
characterised by progressive neuromuscular deterioration and accumulation of lactate and hydrogen ions in blood, urine and/or cerebrospinal fluid, frequently resulting in early death.
It is an x-linked dominant disease affecting both sexes.

12. Arsenic poisoning It inhibits lipoic acid.
Epidemiological evidence shows an association between inorganic arsenic in drinking water and increased risk of skin, lung and bladder cancers

13. Beriberi
A vitamin-deficiency disease first described in 1630 by Jacob Bonitus, a Dutch physician working in Java The term beriberi is derived from the Sinhalese word meaning “extreme weakness.”

14. Beriberi
It is a nutritional disorder caused by a deficiency of thiamin (vitamin B1) and characterized by impairment of the nerves and heart.
In the form known as dry beriberi, there is a gradual degeneration of the long nerves, first of the legs and then of the arms, with associated atrophy of muscle and loss of reflexes.
In wet beriberi, a more acute form, there is edema resulting largely from cardiac failure and poor circulation. In infants breast-fed by mothers who are deficient in thiamin, beriberi may lead to rapidly progressive heart failure.

15. Wernicke–Korsakoff syndrome
This is found predominantly in alcoholics. Chronic alcohol consumption can result in thiamine deficiency by causing inadequate nutritional thiamine intake, decreased absorption of thiamine from the gastrointestinal tract, and impaired thiamine utilization in the cells.
People differ in their susceptibility to thiamine deficiency, however, and different brain regions also may be more or less sensitive to this condition.

16. The Citric Acid Cycle
Step 1: Formation of citrate by condensation of acetyl-CoA with oxaloacetate; G°’= kJ•mol-1
citrate synthase (condensing E) is an allosteric enzyme, inhibited by NADH, ATP, and succinyl-CoA C H 3 - S o A
Acetyl-CoA O 2
Oxaloacetate +
Coenzyme A c
itrate
synthase
Citrate
(3 carboxyl groups)

17. The Citric Acid Cycle
Step 2: dehydration and rehydration gives isocitrate; catalyzed by aconitase(-by flouroacetate rat poison).
citrate is achiral; it has no stereocenter
isocitrate is chiral; it has 2 stereocenters and 4 stereoisomers are possible
only one of the 4 stereoisomers of isocitrate is formed in the cycle C - O H 2
Citrate
Aconitate
Isocitrate
(3 carboxyl groups)

18. The Citric Acid Cycle
Step 3: oxidation of isocitrate followed by decarboxylation
isocitrate dehydrogenase is an allosteric enzyme; it is inhibited by ATP and NADH, activated by ADP and NAD+ C - O H 2
Isocitrate N A D + a
-Ketoglutarate
(2 carboxyl groups)
isocitrate
dehydrogenase
Oxalosuccinate

19. The Citric Acid Cycle Step 4: oxidative decarboxylation of
-ketoglutarate to succinyl-CoA
like pyruvate dehydrogenase, this enzyme is a multienzyme complex and requires coenzyme A, thiamine pyrophosphate, lipoic acid, FAD, and NAD+
DG0’ = kJ•mol-1 C H 2 - O a
-Ketoglutarate o A S N D +
-ketoglutarate
dehydrogenase
complex
Succinyl-CoA
(1 carboxyl groups)

20. The Citric Acid Cycle Step 5: formation of succinate
The two CH2-COO- groups of succinate are equivalent
This is the first energy-yielding step of the cycle
The overall reaction is slightly exergonic C H 2 - O S o A
Succinyl-CoA G D P + i
Succinate
(2 carboxyl groups) T
succinyl-CoA
synthetase

21. The Citric Acid Cycle Step 6: oxidation of succinate to fumarate2 C - O
Succinate
succinate
Dehydrogenase
+Fe, - heme
Fumarate
(2 carboxyl groups)
Note: succinate dehydrogenase is the only TCA enzyme that is located in the inner mitochondrial membrane and linked directly to ETC

22. The Citric Acid Cycle Step 7: hydration of fumarate
Step 8: oxidation of malate C H O -
Fumarate 2
L-Malate
(2 carboxyl groups)
fumarase C - O H 2
Oxaloacetate
(2 carboxyl groups) N A D +
malate
dehydrogenase
L-Malate

23. From Pyruvate to CO2

24. Summary
The two-carbon unit needed at the start of the citric acid cycle is obtained by converting pyruvate to acetyl-CoA
This conversion requires the three primary enzymes of the pyruvate dehydogenase complex, as well as, the cofactors TPP, FAD, NAD+, and lipoic acid
The overall reaction of the pyruvate dehydogenase complex is the conversion of pyruvate, NAD+, and CoA-SH to acetyl-CoA, NADH + H+, and CO2

26. Control of the CA Cycle Three control points within the cycle
citrate synthase: inhibited by ATP, NADH, and succinyl CoA; also product inhibition by citrate
isocitrate dehydrogenase: activated by ADP and NAD+, inhibited by ATP and NADH
-ketoglutarate dehydrogenase complex: inhibited by ATP, NADH, and succinyl CoA; activated by ADP and NAD+
One control point outside the cycle
pyruvate dehydrogenase: inhibited by ATP and NADH; also product inhibition by acetyl-CoA

27. Control of the CA Cycle
Conversion of pyruvate to acetyl-CoA

28. Cells in a resting metabolic state
Cells in an active metabolic state
need and use comparatively little energy
need and use more energy than resting cells
high ATP, low ADP imply high ATP/ADP ratio
low ATP, high ADP imply low ATP/ADP ratio
high NADH, low NAD+ imply high NADH/NAD+ ratio
low NADH, high NAD + imply low NAHDH/NAD+ ratio

29. Why Is the Oxidation of Acetate So Complicated?

30. Because ……………
Besides its role in the oxidative catabolism of carbohydrates, fatty acids, and amino acids, the cycle provides precursors for many biosynthetic pathways.
It is also important for plants and bacteria

31. Glyoxalate Cycle…..

32. Glyoxalate Cycle
Bacteria and plants can synthesize acetyl CoA from acetate and CoA by an ATP-driven reaction that is catalyzed by
acetyl CoA synthetase.

34. Biosynthetic Roles of the Citric Acid Cycle
Biosynthetic Roles of the Citric Acid Cycle. Intermediates drawn off for biosyntheses (shown by red arrows) are replenished by the formation of oxaloacetate from pyruvate.

35. End
Chapter 19