Transcript The Citric Acid Cycle

The Citric Acid Cycle
Dr. Sooad Al-Daihan
Biochemistry department
Introduction
 Also called citric acid cycle or the Krebs cycle
(after its discoverer, Hans Krebs).
 TCA cycle is a series of reactions catalyzed by different
enzymes in which acetyl CoA is oxidized into CO2, H2O
and energy.
 It occurs in the mitochondrial matrix aerobically.
 The enzymes involved in the TCA cycle are present in the
mitochondrial matrix either free or attached to the inner
surface of the mitochondrial membrane.
Continue..
 The citric acid cycle is the final common pathway for the
oxidation of fuel molecules:
amino acids, fatty acids and carbohydrates.
 Most fuel molecules enter the cycle as acetyl coenzyme A.
 The function of the citric acid cycle is the harvesting of high-
energy electrons from carbon fuels.
Continue..
 The citric acid cycle itself neither generates a large amount of
ATP nor includes oxygen as a reactant.
 Instead, the citric acid cycle removes electrons from acetyl
CoA and uses these electrons to form NADH and FADH2.
 The citric acid cycle includes a series of oxidation-reduction
reactions that result in the oxidation of an acetyl group to
two molecules of carbon dioxide.
The citric acid cycle oxidizes two-carbon units, producing
two molecules of CO2, one molecule of GTP, and highenergy electrons in the form of NADH and FADH2.
The amphibolic nature of TCA cycle
 The citric acid cycle is the gateway to the aerobic metabolism of
any molecule that can be transformed into an acetyl group.
 The cycle is also an important source of precursors, not only for the
storage forms of fuels, but also for the building blocks of many
other molecules such as amino acids, nucleotide bases, cholesterol,
and porphyrin.
This pathway is utilized for both catabolic
reactions to generate energy & anabolic
reactions
to
generate
metabolic
intermediates for biosynthesis.
Metabolic pathway
 In oxidative phosphorylation, electrons released in the
reoxidation of NADH and FADH2 flow through a series of
membrane proteins to generate a proton gradient across the
membrane.
 In TCA, the removal of high-energy
electrons from carbon fuels.
 These electrons reduce O2 to generate a
proton gradient .
Which is used to synthesize ATP .
 The
citric acid cycle, in conjunction with oxidative
phosphorylation, provides the vast majority of energy used
by aerobic cells in human beings, greater than 95%.
The TCA Cycle Has Eight Steps
Continue..
 Step 1: Formation of Citrate
- An irreversible reaction catalyzed by citrate synthase.
-Inhibited by: ATP , NADH, Citrate.
Step 2: Formation of Isocitrate
-A reversible reaction catalyzed by aconitase .
Step 3: Oxidative decarboxylation of isocitrate
-The enzyme isocitrate dehydrogenase catalyzes the irreversible
oxidative decarboxylation of isocitrate to form α-ketoglutarate and
CO2.
-Stimulated by: isocitrate, NAD+, Mn2+, ADP, Ca2+.
-Inhibited by: NADH and ATP.
Continue..
Step 4: Oxidative decarboxylation of α-ketoglutarate
-In this irreversible reaction, α-ketoglutarate is converted to succinyl-CoA
and CO2 by the action of the α-ketoglutarate dehydrogenase complex .

-α-ketoglutarate dehydrogenase complex closely resembles the
PDH complex in both structure and function.
-NAD+ serves as electron acceptor and CoA as the carrier of the succinyl
group.
- Inhibited by: NADH, ATP, Succinyl-CoA
- Stimulated by: Ca2+
Continue.
Step 5: Conversion of succinyl-CoA to succinate 
-Reversible reaction catayzed by succinyl-CoA synthetase (succinate
thiokinase)
-Results in the formation of GTP and CoA-SH
-Nucleoside diphosphate kinase interconverts GTP and ATP by a readily
reversible phosphoryl transfer reaction:
GTP + ADP
GDP + ATP
Continue..
 Step 6: Oxidation of Succinate to Fumarate.
- Succinate is oxidized to fumarate by the flavoprotein succinate
dehydrogenase
- Only TCA cycle enzyme contained within the mitochondrial
membrane.
- Results in the formation of FADH2
Continue..
Step 7: Hydration of fumarate to malate 
-The reversible hydration of fumarate to L-malate is catalyzed
by fumarase .
Step 8: Oxidation of malate to oxaloacetate 
-In the last reaction of the citric acid cycle, NAD-linked Lmalate dehydrogenase catalyzes the oxidation of L-malate to
oxaloacetate.
Enzyme Control of the TCA Cycle
Inhibitors of TCA Cycle
 Fluoroacetyl CoA:
-It inhibits aconitase enzyme
-It combines with oxaloacetate giving rise to fluorocitrate .
 Malonic acid:
-Inhibits
succinate
dehydrogenase
(competitive
inhibition)
 Arsenate and Mercury :
-Inhibit Pyruvate dehydrogenase and α-ketoglutarate
dehydrogenase complexs.
- By reacting with sulphydral group of lipoic acid leading
to accumulation of pyruvic lactic acid and αketoglutarate.
Products of Kreb’s Cycle
 2 CO2
 3 NADH
 1 ATP
Per 1 Acetyl CoA (double for 1 glucose)
 1 FADH2
 ATP Yield:
• Each NADH yields 3 ATP
• Each FADH2 yields 2 ATP
Summary of total energy yield of complete
oxidation of 1 glucose molecule
Step
Coenzyme
Yield
ATP
Yield
Source of ATP
Glycolysis –Stage 1
- 2 Phosphorylation of glucose and
fructose uses 2 ATP
Glycolysis –Stage 2
4 Substrate level phosphorylation
Pyruvate metabolism
2 NADH
6 Oxidative phosphorylation
2 NADH
6 Oxidative phosphorylation
TCA cycle
Total Yield
2 Substrate level phosphorylation
6 NADH
18 Oxidative phosphorylation
2 FADH2
4 Oxidative phosphorylation
38 ATP