The citric acid cycle involves 8 steps where oxaloacetate initiates and regenerates the cycle. Acetyl-CoA enters the cycle and is oxidized, producing NADH and FADH2 that feed into the electron transport chain. The cycle is regulated by substrate supply, allosteric effectors, and covalent modification of enzymes. Key enzymes like citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase are regulated. The cycle produces most cellular energy and is important for harvesting electrons from fuels.

1. The citric acid cycle
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3.  The 4c, OAA initiates the first step in TCA cycle and
regenerated at the end of one passage through the
cycle.
 The OAA acts catalytically, it participates in oxidation
of acetyl group but is itself get generated
 Thus one molecule of OAA is capable of participating
in the oxidation of man acetyl molecules
Role of oxaloacetata

5. 1. Formation of Citrate

6. 2. Formation of Isocitrate via cis-
Aconitate

7.  Aconitase is an iron sulfur protein, or non heme iron
protein
 Fluoroacetate is toxic, cause fluroacetyl co-A
condenses with OAA to form fluorocitrate, which
further inhibit aconitase
 This is suicidal inhibition

8. Aconitase has More than One Role
Mitochondrial aconitase: Citric Acid Cycle
Cytosolic aconitase: 2 roles:
1. citrate  isocitrate
2. iron response regulator

9. 3. Oxidation of Isocitrate to Ketoglutarate and CO2

10. 4. Oxidation of -Ketoglutarate to Succinyl-CoA
and CO2

11.  α -ketoglutarate dehydrogenase complex
closely resembles the PDH complex in both
structure and function.
 It includes three enzymes, homologous to E1,
E2, and E3 of the PDH complex, as well as
enzyme-bound TPP, bound lipoate, FAD, NAD,
and coenzyme A.

12.  Unidirectional type
 Arsenite inhibit the enzyme

13. 5. Conversion of Succinyl-CoA to Succinate

14. 6. Oxidation of Succinate to Fumarate

15.  Malonate, an analog of succinate not normally
present in cells, is a strong competitive
inhibitor of succinate dehydrogenase and its
addition to mitochondria blocks the activity of
the citric acid cycle.

16. 7. Hydration of Fumarate to Malate

17. 8. Oxidation of Malate to Oxaloacetate

19.  3 hydride ion (6 electron) are transferred to 3 mol of
NAD+ and 2 hydrogen atom (2 eletron) are
transferred to FAD+.
 The function of TCA cycle is the harvesting of high
energy electron from carbon fuels
 TCA removes electron from acetyl co-A and uses
these to form NADH and FADH2
 In oxidative phosphorylation electron released in the
reoxidation of those reducing equivalents and flow
through a series of membrane protein in ETC.
 TCA cycle will provide majority of energy used ie
around 95%

21. ENERGY PRODUCED BY THE TCA CYCLE

22.  The flow of carbon atoms from pyruvate into
and through the citric acid cycle is under tight
regulation at two levels:
1. The conversion of pyruvate to acetyl-CoA,
the starting material for the cycle and
2. The entry of acetyl-CoA into the cycle (the
citrate synthase reaction).
Regulation of the Citric Acid Cycle

23.  The cycle is also regulated at the isocitrate
dehydrogenase and α –ketoglutarate
dehydrogenase reactions.

24.  Allosteric modification
Acetyl coA, NADH inhibit
CoA, NAD+ activate
 Covalent modification
State of phosphorylation
Kinases and phosphatase will help
PDH complex is activates in dephosphorylated state
Regulation of PDH complex

26. Regulation of the Citric Acid Cycle
• Pathway controlled by:
(1) Allosteric modulators
(2) Covalent modification of cycle enzymes
(3) Supply of acetyl CoA (pyruvate dehydrogenase
complex)
Three enzymes have regulatory properties
- citrate synthase (is allosterically inhibited by NADH, ATP,
succinyl CoA, citrate – feedback inhibition)
- isocitrate dehydrogenase
(allosteric effectors: (+) ADP; (-) NADH, ATP. Bacterial ICDH
can be covalently modified by kinase/phosphatase)
--ketoglutarate dehydrogenase complex (inhibition by ATP,
succinyl CoA and NADH

28.  Aconitase inhibited by fluoro acetate, non
competitive inhibition
 α ketoglutarate DH inhibited by arsenite, non
competitive inhibition
 Succinate DH inhibited by malonate, competitive
inhibition
Inhibitors

29.  Riboflavin
 Niacin
 Thiamine
 Pantothenic acid
 Biotin
Role of vitamins

30. Thank you……..