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ELECTRON TRANSPORT CHAIN:

-Biological oxidations are catalyzed by intracellular enzymes. The purpose of oxidation is to obtain energy. -Electron Transport: Electrons carried by reduced coenzymes (NADH or FADH2) are passed sequentially through a chain of proteins and coenzymes (so called electron transport chain)to O2. -Oxidative Phosphorylation: Coupling e-Transport (Oxidation) and ATP synthesis (Phosphorylation) . -It all happens in mitochondrionor at the inner mitochondrial membrane(eukaryotic cells).

Mitochondria:
outer membrane relatively permeable inner membrane permeable only to those things with specific transporters Impermeable to NADH and FADH2 Permeable to pyruvate Compartmentalization Kreb's and -oxidation in matrix Glycolysis in cytosol the mitochondrion contained the enzymes responsible for electron transport and oxidative phosphorylation

REDOX POTENTIALS: Redox potential is a capacity to hold electrons within itself.Molecules with lower standard redox potential have higher capacity to donate electrons.Higher standard redox potential have capacity to accept electrons from molecules with lower standard redox potential. Nernst equation:

=Standard redox potential = Standard free energy change n= number of electrons transferred F= faraday constant (96485 J/volt/mole) Electrons move from higher to lower standard free energy change. -Removal of H across a C-C bond is not sufficiently exergonic to reduce NAD+,but it does yield enough energy to reduce FAD. -Thats why succinate dehydrogenase uses FAD other than NAD+as coenzyme. Most energy from Redox: electrons during metabolic reactions sent to NAD and FAD Glycolysis In cytosol produces 2 NADH Pyruvate dehydrogenase reaction In mitochondrial matrix 2 NADH / glucose Krebs In mitochondrial matrix 6 NADH and 2 FADH2/ glucose

ELECTRON CARRIERS:

-The transfer of electrons is not directly to oxygen but through coenzymes. -There are 2 sites of entry for electrons into the electron transport chain: NAD+ or FAD Both are coenzymes for dehydrogenase enzymes. Nicotinamide coenzymes: NAD+ Always a 2-electron reaction transferring 2 e- and 2 H+ The flavin coenzymes / flavoproteins : -flavin adenine dinucleotide (FAD) always a 2-electron reaction transferring 2 e- and 2 H+ -it can accept/donate 1 or 2 e-.FMN has an important role in mediating etransfer between carriers that transfer 2 e-(e.g., NADH) and those that transfer 1 e-(e.g., Fe+++). Iron-sulfur Centers (clusters) -Iron-sulfur centers (Fe-S) are prosthetic groups containing 1-4 iron atoms Iron-sulfur centers transfer only one electron, even if they contain two or more iron atoms. Ubiquinone Coenzyme Q(CoQ, Q or ubiquinone) is lipid-soluble. It dissolves in the hydrocarbon core of a membrane. the only electron carrier not bound to a protein. it can accept/donate 1 or 2 e-.Q can mediate e-transfer between 2 e-that transfer and 1 e-carriers Cytochromes -proteins that accept electrons from QH2 or FeS -Ultimately transfers the electrons to oxygen. -Cytochromesare electron carriers containing hemes . Hemes in the 3 classes of cytochrome (a,b,c) differ in substituents on the porphyrin ring. -Some cytochromes(b,c1,a,a3) are part of large integral membrane protein complexes. -Cytochrome c is a small, water-soluble protein. THE ELECTRON TRANSPORT CHAIN:

Support for this order of events: 1. Energetically favorable. electrons pass from lower to higher standard reduction potentials 2. Spectra: the absorption spectrum for the reduced carrier differs from that of its oxidized form. carriers closer to oxygen are more oxidized. 3. Specific inhibitors. Those before the blocked step should be reduced and those after be oxidized.4. Assay of individual complexes.NADH can reduce complex I but not the other complexes COMPLEX 1: Has NADH binding site NADH reductase activity NADH -NAD+ NADH ---> FMN--->FeS---> ubiquinone ubiquinone ---> ubiquinone H2 4 H+pumped/NADH

NADH + H++ Q NAD++ QH2

COMPLEX 2: succinate ---FADubiquinone Contains coenzyme Q FADH2binding site FAD reductase activity FADH2--FAD Reason for no proton pump by complex 2: 1)It is not a transmembrane protein and hence cannot pump proton from matrix to intermembrane space. 2) E produced by electron transfer in complex 2 is so small that it cannot pump proton from matrix to intermembrane space,because it produces very small G. COMPLEX 3: ubiquinone -ubiquinone ox while cyt C gets reduced Also contains cytochromes b proton pump 4H+ Adds to gradient 8 H+/ NADH 4 H+/ FADH2 COMPLEX 4: -reduction of oxygen -cytochrome oxidase -cyt a+a3 red---> oxidized state -oxygen ---> water 2 H++ 2 e-+ O2-transfers e-one at a time to oxygen -Pumps 2H+out Total of 10 H+/ NADH Total of 6 H+/ FADH2

INHIBITORS OF ETS:
Complex 1= Rotenone,Amytol Complex 2= Malonate,Carboxyn Complex 3= Antimycin,Mixothiozole,Dimercaparol Complex 4= Cyanite, Azide, Carbon monoxide.(These three inhibitor are known as warburg inhibitor. UNCOUPLER: A) Synthetic uncoupler: 2,4-dinitrophenol,dicumarol Uncoupler has two properties: -It should be hydrophobic which help its movement in mitochondrial membrane -It should have ionizable group which can carry a proton from intermembrane space to matrix. Uncoupler has 2 stages, one is protonated and other is deprotonated.Proton is taken from intermembrane space and release into matrix by these uncoupler which finally function just reverse to the pump which decrease the electrochemical gradient and ATP synthesis. B) Natural uncoupler: Ionophores are antibiotics that generate pore in membrane to kill the bacteria. Valonomycin decrease membrane potential component of proton motive force without direct effect on pH gradient . Nigericin disrupt the chemical gradient without changing membrane potential. SHUTTLE SYSTEM: NADH made in cytosol Cant get into matrix of mitochondrion 2 mechanisms In muscle and brain Glycerol phosphate shuttle In liver and heart Malate / aspartate shuttle GLYCEROL PHOSPHATE SHUTTLE:

In muscle and brain Each NADH converted to FADH2inside mitochondrion FADH2enters later in the electron transport chain Produces 1.5 ATP Total ATP per glucose in muscle and brain Gycerol phosphate shuttle

2 NADH per glucose -2 FADH2 2 FADH2X 1.5 ATP / FADH2.3.0 ATP 2 ATP in glycoysis2.0 ATP From pyruvate and Krebs 12.5 ATP X 2 per glucose ..25.0 ATP Total = 30.0 ATP/ glucose MALATE ASPARTATE SHUTTLE:

Malate Aspartate Shuttlein cytosol


In liver and heart

NADH oxidized while reducing oxaloacetate to malate


Malate dehydrogenase

Malate crosses membrane

Malate Aspartate Shuttlein matrix


Malate reoxidized to oxaloacetate
Malate dehydrogenase NAD+reduced to NADH

NADH via electron transport yields 2.5 ATP

Total ATP per glucose in liver and heart


Malate Aspartate Shuttle
2 NADH per glucose -2 NADH

2 NADH X 2.5 ATP / NADH5.0 ATP 2 ATP from glycolysis..2.0 ATP From pyruvate and Krebs
12.5 ATP X 2 per glucose ..25.0 ATP
Total = 32.0 ATP/ glucose

Summary
Total ATP / glucose
Muscle and brain30.0 ATP
Uses glycerol phosphate shuttle

Heart and liver32.0 ATP


Uses malate aspartate shuttle

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