The Citric Acid Cycle Dr. Sooad Al-Daihan Biochemistry department

The Citric Acid CycleThe Citric Acid Cycle

Dr. Sooad Al-DaihanDr. Sooad Al-DaihanBiochemistry department Biochemistry department

IntroductionIntroduction Also called citric acid cycle citric acid cycle or the Krebs cycleKrebs 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.

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.acetyl coenzyme A. The function of the citric acid cycle is the harvesting of high-energy electrons from carbon fuels.

ContinueContinue....


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 The citric acid cycle oxidizes two-carbon units, producing two molecules of CO2, one units, producing two molecules of CO2, one molecule of GTP, and high-energy electrons molecule of GTP, and high-energy electrons in the form of NADH and FADH2in the form of NADH and FADH2..

The amphibolic nature of TCA cycleThe amphibolic nature of TCA cycle The citric acid cycle is the gateway to the aerobic metabolism 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 storage forms of fuels, but also for the building blocks 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 pathwayMetabolic pathway In oxidative phosphorylationoxidative 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.

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%.

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 TCA Cycle Has Eight StepsThe TCA Cycle Has Eight Steps

Step 1:Step 1: Formation of Citrate - An irreversible reaction catalyzed by citrate synthase.citrate synthase.

-Inhibited by: -Inhibited by: ATP , NADH, Citrate.Step 2:Step 2: Formation of Isocitrate-A reversible reaction catalyzed by aconitase .Step 3: Step 3: Oxidative decarboxylation of isocitrate -The enzyme isocitrate dehydrogenase isocitrate dehydrogenase catalyzes the irreversible oxidative decarboxylation of isocitrate to form α-ketoglutarate and CO2.

-Stimulated by: Stimulated by: isocitrate, NAD+, Mn2+, ADP, Ca2+.-Inhibited by: Inhibited by: NADH and ATP.


Step 4: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-α-ketoglutarate dehydrogenase complex .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: Inhibited by: NADH, ATP, Succinyl-CoA- Stimulated by: Stimulated by: Ca2+


ContinueContinue..Step 5: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

Step 6: Oxidation of Succinate to Fumarate. - Succinate is oxidized to fumarate fumarate by the

flavoprotein succinate dehydrogenase succinate dehydrogenase - Only TCA cycle enzyme contained within the

mitochondrial membrane.- Results in the formation of FADHFADH22


ContinueContinue....Step 7:Step 7: Hydration of fumarate to malate-The reversible hydration of fumarate to L-

malate is catalyzed by fumarase.

Step 8:Step 8: Oxidation of malate to oxaloacetate

-In the last reaction of the citric acid cycle, NAD-linked L-malate dehydrogenase catalyzes the oxidation of L-malate to

oxaloacetate .

Enzyme Control of the TCA CycleEnzyme Control of the TCA Cycle

Inhibitors of TCA CycleInhibitors of TCA CycleFluoroacetyl CoA: Fluoroacetyl CoA: -It inhibits aconitase enzyme -It combines with oxaloacetate giving rise to fluorocitrate .Malonic acid: Malonic acid: -Inhibits succinate dehydrogenase (competitive inhibition) Arsenate and Mercury : Arsenate and Mercury : -Inhibit Pyruvate dehydrogenase and -ketoglutarate α

dehydrogenase complexs.- By reacting with sulphydral group of lipoic acid leading to

accumulation of pyruvic lactic acid and - ketoglutarate. α

Products of KrebProducts of Kreb’’s Cycles Cycle2 CO2

3 NADH1 ATP Per 1 Acetyl CoA (double for 1 glucose)

1 FADH2

ATP Yield:ATP Yield:• Each NADH yields 3 ATP• Each FADH2 yields 2 ATP

Summary of total energy yield of complete Summary of total energy yield of complete oxidation of 1 glucose moleculeoxidation of 1 glucose molecule

StepCoenzyme Yield

ATP Yield

Source of ATP

Glycolysis –Stage 1

-2Phosphorylation of glucose and fructose uses 2 ATP

Glycolysis –Stage 2

4Substrate level phosphorylation

2 NADH6Oxidative phosphorylation

Pyruvate metabolism


TCA cycle2Substrate level phosphorylation


2 FADH24Oxidative phosphorylation

Total Yield38 ATP

Documents

The Citric Acid Cycle Dr. Sooad Al-Daihan Biochemistry department