The Citric Acid Cycle and Electron Transport Chain

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Preparing Pyruvate

In order to enter the Citric Acid Cycle pyruvate must:

  • Pass from the cytosol of the cell into the mitochondrion (via membrane transport protein)
  • Be converted to Acetyl Coenzyme A


  • An acyl group carrier
  • Referred to as CoA
  • Written in equations as CoA-SH as the thiol group is the reactive part
  • Carries acyl groups as thiol esters (high energy compounds)
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Acetyl CoA formation


Pyruvate enters the mitcohondrial matrix and is converted to Acetyl CoA

Acetyl group enters the citric acid cycle

Enzyme used: pyruvate dehydrogenase

The overall process is oxidative decarboxylation as a carbon is removed as CO2

Two carbons are transferred as an acetyl unit

Two electrons and two hydrogens are transferred to NAD

Acetyl CoA is also generated by break down of fatty acids

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Citric Acid Cycle - Synthesis of Citrate

2-C transferred to AcetylCoA are now ready to enter the cycle.

Feature: uses free energy available from destruction of the Acetyl group to drive the cycle - thermodynamically

Purpose: to produce H+ and e- that are transferred to NAD+ and FAD.

NADH and FADH2 are utitlised in the Electron Transport System to produce ATP.

ACETYL COA + OXALOACETATE ====> CITRATE               catalysed by citrate synthase

Acetyl CoA enters the cycle by reaction with oxaloacetate to form citrate - requiring an input of water.

This reaction is accompanied by a loss of free energy (as heat) and is irreversible. It is a highly regulated step, as a metabolic branch point.

After one complete turn of the cycle, oxaloacetate is re-formed and the acetyl group has disappeared

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Citrate to Isocitrate

CITRATE =======> ISOCITRATE               catalysed by aconitase

Strategy: to switch the hydroxyl group of citrate (symmetrical) from 3 position to 2 position (asymmetrical)

Reversible reaction

Citrate is important for biosynthetic reactions

DeltaG (free energy) is negative for this reaction

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Decarboxylation of Isocitrate


catalysed by isocitrate dehydrogenase

Stimulated by NAD+ and ADP

Inhibited by NADH and ATP

Commits citrate to the citric acid cycle

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Decarboxylation of A-Ketoglutarate


catalysed by a-ketoglutarate dehydrogenase complex

Alpha-ketoglutarate is decarboxylated to form succinyl-CoA (high energy thio-ester)

Metabolic branch point, activated by low energy status of cell

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Formation of Succinate


catalysed by succinyl CoA synthetase

Only reaction that generates a high energy phosphate

GTP is converted to ATP or is used in protein synthesis

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Succinate Dehydrogenation


catalysed by succinate dehydrogenase

Enzyme is bound to the inner surface of the mitochondrial membrane 

Directly linked to the ETS

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Hydration of Fumarate


catalysed by fumarase

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Dehydrogenation of Malate


catalysed by malate dehydrogenase

Reaction reforms oxaloacetate

Thermodynamically, malate is the favoured product

In the cell, oxaloacetate concentration is so low because it is constant used that the reaction proceeds anyway.

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Molecules produced in the Citric Acid Cycle

2 molecules of Acetyl CoA enter the Citric Acid Cycle from one molecule of glucose

2 molecules of GTP are formed (can be converted to 2ATP)

6 molecules of NADH formed for the ETC

2 molecules of FADH2 formed for the ETC

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Electron Transport System

Purpose: produce ATP from ADP and Pi using energy from electron movement to oxygen

Electrons flow along a series of electron transport carriers embedded in the membrane.

Each carrier in the series accepts and releases electrons at a lower energy level than the carrier preceding it.

Energy released is used to transport H+ across the mebrane against the concentration gradient

This maintains the H+ gradient to drive ATP synthesis.

Most carriers are:

  • Integral membrane proteins and contain: a non-protein organic group and a prosthetic group containing a metal ion that accepts and releases elctrons
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Complexes in the ETC


Conducts electrons from NADH to ubiquinone


Carries electrons from oxidation of succinate to ubiquinone. FADH2 enters


Conducts electrons from ubiquinone to cytochrome c


Conducts electrons from cytochrom c to oxygen. Inhibited by cyanide

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End of the chain

After travelling down the ETC:

  • Electrons are at lower energy levels
  • Electons pass to a final electron acceptor - oxygen
  • This is converted to water:

O2 + 4H+ + 4e- ===> 2H2O

The energy has been used to create a large concentration gradient of H+.

ATP synthase uses this gradient as an energy source for ATP synthesis

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The Chemiosmotic Theory

As H+ ions are pumped form the matrix to the intermembrane space this generates:

a pH gradient and an electrical gradient as the matrix will be negatively charged relative to the intermembrane space.


An electrochemical gradient has an electrochemical potential energy - the Proton Motive Force

As protons flow back, ATP is produce. Approx 3H+ ions must flow back for every ATP produced.

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Oxidative Phosphorylation

Energy from the flow of protons back through the inner mitochondrial membrane is used by ATP-ase to phosphorylate ADP

ATP synthase is an enzyme composed of two main usits F1 and F0

A binding change occurs when H+ passes through the unit back into the matrix.

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2,4-DNP is a weak acid, so in high H+ concentrations, it will be protonated.

If H+ concentration is low, it will lose a H+ ion.

It is found in membranes due to its hydrophobicity.

Therefore ATP synthesis decreases in the presence of 2,4-DNP.

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ETC and Oxidative Phosphorylation

ETC and Oxidative Phosphorylation are coupled via the energy provided from the ETC.

If they become uncoupled (e.g. with 2,4-DNP), energy is lost as heat resulting in weight loss

Extensive uncoupling leads to liver damage and DEATH

In total, 32 ATP molecules are produced from cellular respiration

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