Citric Acid Cycle | Krebs Cycle | TCA cycle

This slide contains details of Citric Acid Cycle along with its pathway.

2. Citric Acid Cycle (Krebs Cycle or
TricarboxylicAcid—TCA cycle)
•The citric acid cycle is the most important metabolic
pathway for the energy supply to the body. About 65-
70% of the ATP is synthesized in Krebs cycle. 70% of the ATP is synthesized in Krebs cycle.
•Citric acid cycle essentially involves the oxidation of
acetyl CoAto CO2 and H2O.
•This cycle utilizes about two-thirds of total oxygen
consumed by the body. The name TCA cycle is used,
since, at the outset of the cycle, tricarboxylicacids
(citrate, cisaconitateand isocitrate) participate.

3. TCA cycle—an overview
•It involves the combination of a two carbon
acetyl CoAwith a four carbon oxaloacetateto
produce a six carbon tricarboxylicacid, citrate. In
the reactions that follow, the two carbons are the reactions that follow, the two carbons are
oxidized to CO2 and oxaloacetateis regenerated
and recycled.
•Oxaloacetateis considered to play a catalytic
role in citric acid cycle.

4. (Citric Acid Cycle) Step I
•Formation of citrate : Krebs cycle proper
starts with the condensation of acetyl CoAand
oxaloacetate, catalysedby the enzyme citrate
synthase.synthase.

5. (Citric Acid Cycle) Step I -Continued

6. (Citric Acid Cycle) Step II & III
•Citrate is isomerizedto isocitrateby the
enzyme aconitase.
•This is achieved in a two stage reactionof •This is achieved in a two stage reactionof
dehydration followed by hydration through
the formation of an intermediate—cis-
aconitate.

7. (Citric Acid Cycle) Step II & III -Continued

8. (Citric Acid Cycle) Step IV & V
•Formation of -ketoglutarate: The enzyme
isocitratedehydrogenase(ICD) catalyses the
conversion (oxidative decarboxylation) of
isocitrateto oxalosuccinateand then to -isocitrateto oxalosuccinateand then to -
ketoglutarate.
•The formation of NADH and the liberation of
CO2 occur at this stage.

9. (Citric Acid Cycle) Step IV & V -Continued

10. (Citric Acid Cycle) Step VI
•Conversion of -ketoglutarateto succinylCoA
occurs through oxidative decarboxylation,
catalysedby -ketoglutaratedehydrogenase
complex. complex.
•The mechanism of the reaction is analogous to
the conversion of pyruvateto acetyl CoA

11. (Citric Acid Cycle) Step VI -Continued

12. (Citric Acid Cycle) Step VII
•Formation of succinate: SuccinylCoAis
converted to succinateby succinatethiokinase.
This reaction is coupled with the phosphorylation
of GDP to GTP. of GDP to GTP.
•This is a substrate level phosphorylation.
•GTP is converted to ATP by the enzyme
nucleoside diphosphatekinase.
•GTP + ADP ATP + GDP

13. (Citric Acid Cycle) Step VII -Continued

14. (Citric Acid Cycle) Step VIII
•Conversion of succinateto fumarate: Succinate
is oxidized by succinatedehydrogenaseto
fumarate.
•This reaction results in the production of FADH2
and not NADH.

15. (Citric Acid Cycle) Step VIII -Continued

16. (Citric Acid Cycle) Step IX
•Formation of malate: The enzyme fumarase
catalyses the conversion of fumarateto
malatewith the addition of H2O.

17. (Citric Acid Cycle) Step IX -Continued

18. (Citric Acid Cycle) Step X
•Conversion of malateto oxaloacetate: Malateis
then oxidized to oxaloacetateby malate
dehydrogenase.
•The third and final synthesis of NADH occurs at •The third and final synthesis of NADH occurs at
this stage.
•The oxaloacetateis regenerated which can
combine with another molecule of acetyl CoA,
and continue the cycle.

19. (Citric Acid Cycle) Step X -Continued

20. Pathway of Citric acid cycle:
Diagram/Pictorial RepresentationDiagram/Pictorial Representation

21. Sample 1

22. Sample 2

23. Energeticsof TCA cycle
Step
No.
Enzyme CoenzymeATPsgenerated
4IsocitratedehydrogenaseNADH 3
6 -Ketoglutarate NADH 36 -Ketoglutarate
dehydrogenase
NADH 3
7Succinicthiokinase GTP 1
8SuccinatedehydrogenaseFADH2 2
10MalatedehydrogenaseNADH 3
Total ATPsgenerated 12

24. Energeticsof TCA cycle
•During the process of oxidation of acetyl CoAvia
citric acid cycle, 4 reducing equivalents (3 as NADH
and one as FADH2) are produced.
•Oxidation of 3 NADH by electron transport chain
coupled with oxidative phosphorylationresults in
•Oxidation of 3 NADH by electron transport chain
coupled with oxidative phosphorylationresults in
the synthesis of 9 ATP, whereas FADH2 leads to the
formation of 2 ATP. Besides, there is one substrate
level phosphorylation.
•Thus, a total of twelve ATP are produced from one
acetyl CoA.

25. Significance
TCA cycle is the final common oxidative pathway for all
the major ingredients of food stuffs. carbohydrates enter
via pyruvateand acetyl CoA. ratty acids are broken down
into acetyl CoA. Amino acids, after transaminationenter
in this cycle. in this cycle.
Without carbohydrates, fat cannot be metabolised,
because for complete oxidation of fat, oxaloacetateis
required, which is formed from pyruvate. Oxaloacetate
acts as a true catalyst, as it enters in the cycle but is
regenerated at the end.

26. Significance
Excess carbohydrate is converted to neutral fats which are
stored in the body. The pathway for the formation of
neutral fat is: Glucose PyruvateAcetyl CoAFatty
acid. The conversion of pyruvateto acetyl CoAis catalysed
by pyruvatedehydrogenase, which is an irreversible
reaction. Hence, fat cannot be converted to glucose.
by pyruvatedehydrogenase, which is an irreversible
reaction. Hence, fat cannot be converted to glucose.
Most amino acids enter in TCA cycle after deamination. For
example, glutamicacid enters at -ketoglutaratewhereas
aspartateenters at oxaloacetate. These amino acids which
are converted as members of the cycle can also enter in
gluconeogenesisvia oxaloacetate. Such amino acids are
called gluconeogenicamino acids.

27. Significance
The amino acids like leucine, are metabolisedto acetyl
CoA. Acetyl CoAeither enters TCA cycle and gets
completely oxidisedor is channeled to ketonebody
formation. Such amino acids are called as ketogenic.
All other pathways are either catabolic or anabolic, but All other pathways are either catabolic or anabolic, but
TCA cycle is purely amphibolici.e. catabolic + anabolic.
TCA cycle acts as a source for the precursors of
biosynthetic pathways, e.g. hemeis synthesized from
succinylCoAwhereas aspartateforms oxaloacetate.
This is also called as anapleoroticrole of TCA cycle.

28. Regulation of citric acid cycle
•Three enzymes—namely citrate synthase,
isocitrate dehydrogenase and -ketoglutarate
dehydrogenase-regulate citric acid cycle.

29. Regulation of TCA cycle
Citrate synthaseis inhibited by ATP, NADH, acetyl CoAand succinylCoA.
Isocitratedehydrogenaseis activated by ADP, and inhibited by ATP and
NADH.
Ketoglutaratedehydrogenaseis inhibited by succinylCoAand NADH.
Availability of ADP is very important for the citric acid cycle to proceed. Availability of ADP is very important for the citric acid cycle to proceed.
This is due to the fact that unless sufficient levels of ADP are available,
oxidation (coupled with phosphorylationof ADP to ATP) of NADH and
FADH2 through electron transport chain stops. The accumulation of NADH
and FADH2 will lead to inhibition of the enzymes (as stated above) and
also limits the supply of NAD+ and FAD which are essential for TCA cycle to
proceed.

30. References:
•Biochemistry 5
th
Edition by Dr. U. Satyanarayana& Dr. U. Chakrapani
•Harper’s Illustrated Biochemistry, twenty-sixth edition by Robert K. Murray, Daryl K. Granner, Peter A. Mayes &
Victor W. Rodwell
•Lehninger, Principle of Biochemistry, Fourth edition by David L. Nelson and Michael M. Cox