By:

Mrs. Kalaivani Sathish

Asst Professor
VNC - PANIPAT
 TCA Cycle

 Also known as Krebs cycle

 TCA cycle essentially involves the oxidation of
acetyl CoA to CO2 and H2O.
 TCA cycle –the central metabolic pathway
 The TCA cycle is the final common oxidative
pathway for carbohydrates, fats, amino acids.
 TCA cycle supplies energy & also provides many
intermediates required for the synthesis of amino
acids, glucose, heme etc.
 TCA cycle is the most important central pathway
connecting almost all the individual metabolic
pathways.
 Definition
 Citric acid cycle or TCA cycle or tricarboxylic acid
cycle essentially involves the oxidation of acetyl
CoA to CO2 & H2O.
 Location of the TCA cycle
 Reactions of occur in mitochondrial matrix, in
close proximity to the ETC.
 Reactions of TCA cycle

 Oxidative decarboxylation of pyruvate to acetyl

CoA by PDH complex.
 This step is connecting link between glycolysis and
TCA cycle.
 Reactions of TCA Cycle
 Step:1 Formation of citrate
 Oxaloacetate condenses with acetyl CoA to form
Citrate, catalysed by the enzyme citrate synthase
 Inhibited by:
 ATP, NADH, Citrate - competitive inhibitor of
oxaloacetate.
 Steps 2 & 3 Citrate is isomerized to isocitrate
 Citrate is isomerized to isocitrate by the enzyme
aconitase
 This is achieved in a two stage reaction of
dehydration followed by hydration through the
formation of an intermediate -cis-aconiase
 Steps 4 & 5 Formation of -ketoglutarate
 Isocitrate dehydrogenase (ICDH) catalyses the
conversion of (oxidative decarboxylation) of isocitrate
to oxalosuccinate & then to -ketoglutarate.
 The formation of NADH & the liberation of CO2
occure at this stage.
 Stimulated (cooperative) by isocitrate, NAD+, Mg2+,
ADP, Ca2+ (links with contraction).
 Inhibited by NADH & ATP
 Step: 6 Conversion of -ketoglutarate to
succinyl CoA
 Occurs through oxidative decarboxylation,
catalysed by -ketoglutarate dehydrogenase
complex.
 -ketoglutarate dehydrogenase is an multienzyme
complex.
 At this stage of TCA cycle, second NADH is
produced & the second CO2 is liberated.
 Step: 7 Formation of succinate

 Succinyl CoA is converted to succinate by

succinate thiokinase.
 This reaction is coupled with the phosphorylation
of GDP to GTP.
 This is a substrate level phosphorylation.
 GTP is converted to ATP by the enzyme nucleoside
diphosphate kinase.
 Step: 8 Conversion of succinate to fumarate
 Succinate is oxidized by succinate dehydrogenase
to fumarate.
 This reaction results in the production of FADH2.
 Step: 9 Formation of malate: The enzyme
fumarase catalyses the conversion of fumarate to
malate with the addition of H2O.
 Step:10 Conversion of malate to
oxaloacetate
 Malate is then oxidized to oxaloacetate by malate
dehydrogenase.
 The third & final synthesis of NADH occurs at this
stage.
 The oxaloacetate is regenerated which can
combine with another molecule of acetyl CoA &
continue the cycle.
 Pyruvate
NAD+ PDH
CO2, NADH + H+
Acetyl CoA

Oxaloacatete Citrate Citrate

NAD+ synthase
Aconitase
NADH + H+
Malate Cis-Aconitase
- H2O Fumarase Aconitase
Fumarate TCA
FAD Iso-citrate
SDH
FADH2 NAD+
Succinate NADH + H+
GTP Oxalosuccinate
GDP+Pi Succinyl CoA
ɑ-Ketoglutarate
CO2, NADH + H+
NAD+
 Regeneration of oxaloacetate

 The TCA cycle basically involves the oxidation of

acetyl CoA to CO2 with the simultaneous
regeneration of oxaloacetate.
 There is no net consumption of oxaloacetate or any
other intermediate in the cycle.
 Significance of TCA cycle
 Complete oxidation of acetyl CoA.
 ATP generation.
 Final common oxidative pathway.
 Integration of major metabolic pathways.
 Fat is burned on the wick of carbohydrates.
 Excess carbohydrates are converted as neutral fat
 No net synthesis of carbohydrates from fat.
 Carbon skeleton of amino acids finally enter the TCA cycle.
 Requirement of O2 by TCA cycle

 There is no direct participation of O2 in TCA cycle.

 Operates only under aerobic conditions.

 This is due to, NAD+ & FAD required for the

operation of the cycle can be regenerated in the

respiratory chain only in presence of O2.
 Therefore, citric acid cycle is strictly aerobic.
 Energetics of TCA Cycle

 Oxidation of 3 NADH by ETC coupled with

oxidative phosphorylation results in the synthesis of
9ATP.
 FADH2 leads to the formation of 2ATP.
 One substrate level phosphorylation.
 Thus, a total of 12 ATP are produced from one
acetyl CoA.
 Regulation of TCA Cycle

 Three regulatory enzymes

1. Citrate synthase
2. Isocitrate dehydrogenase
3.α-ketoglutarate dehydrogenase
 Citrate synthase is inhibited by ATP, NADH, acyl
CoA & succinyl CoA.
 Isocitrate dehydrogenase is activated by ADP &
inhibited by ATP and NADH
 α-ketoglutarate dehydrogenase is inhibited by
succinyl CoA & NADH.
 Availability of ADP is very important for TCA
cycle to proceed.
 Transamination

 Transamination is a process where an amino acid

transfers its amino group to a keto group and itself
gets converted to a keto acid.
 The formation of Alpha ketoglutarate &
oxaloacetate occures by this mechanism.
 References

 Textbook of Biochemistry-U Satyanarayana

 Textbook of Biochemistry- DM Vasudevan
Thank You