Oxidative phosphorylation



  Oxidative phosphorylation is a glycolysis.

During oxidative phosphorylation, electrons are transferred from electron transport chains. In eukaryotes, five main protein complexes are involved, whereas in prokaryotes many different enzymes are present, using a variety of electron donors and acceptors.

The energy released as electrons flow through this electron transport chain is used to transport protons across the inner mitochondrial membrane, in a process called phosphorylation reaction. Unusually, the ATP synthase is driven by the proton flow which forces the rotation of a part of the enzyme—it is a rotary mechanical motor.

Although oxidative phosphorylation is a vital part of inhibit their activities.

Overview of energy transfer by chemiosmosis

Further information: Bioenergetics

Oxidative phosphorylation works by using energy-releasing chemical reactions to drive energy-requiring reactions: The two sets of reactions are said to be coupled. This means one cannot occur without the other. The flow of electrons through the electron transport chain, from electron donors such as endergonic process that requires an input of energy.

Both the electron transport chain and the ATP synthase are embedded in a membrane, and energy is transferred from electron transport chain to the ATP synthase by movements of protons across this membrane, in a process called chloroplasts.[2]

ATP synthase releases this stored energy by completing the circuit and allowing protons to flow down the electrochemical gradient, back to the N-side of the membrane.[3] This enzyme is like an electric motor as it uses the proton-motive force to drive the rotation of part of its structure and couples this motion to the synthesis of ATP.

The amount of energy released by oxidative phosphorylation is high, compared with the amount produced by anaerobic fermentation. glucose to carbon dioxide and water.[4] This ATP yield is the theoretical maximum value; in practice, some protons leak across the membrane, lowering the yield of ATP.[5]

Electron and proton transfer molecules

Further information: Coenzyme and Cofactor

  The electron transport chain carries both protons and electrons, passing electrons from donors to acceptors, and transporting protons across a membrane. These processes use both soluble and protein-bound transfer molecules. In mitochondria, electrons are transferred within the intermembrane space by the water-heme group in its structure. Cytochrome c is also found in some bacteria, where it is located within the periplasmic space.[7]

Within the inner mitochondrial membrane, the menaquinone, in addition to ubiquinone.[10]

Within proteins, electrons are transferred between cysteine. Metal ion cofactors undergo redox reactions without binding or releasing protons, so in the electron transport chain they serve solely to transport electrons through proteins. Electrons move through quite long distances in proteins by hopping along between chains of these cofactors.[12] This occurs by quantum tunnelling, which is rapid over distances of less than 14 Å.[13]

Eukaryotic electron transport chains

Further information: Chemiosmosis

Many catabolic biochemical processes, such as Succinate is also oxidized by the electron transport chain, but feeds into the pathway at a different point.

In eukaryotes, the enzymes in this electron transport system use the energy released from the oxidation of NADH to pump electrochemical gradient across the membrane. The energy stored in this potential is then used by ATP synthase to produce ATP. Oxidative phosphorylation in the eukaryotic mitochondrion is the best-understood example of this process. The mitochondrion is present in almost all eukaryotes, with the exception of anaerobic protozoa such as Trichomonas vaginalis that instead reduce protons to hydrogen in a remnant mitochondrion called a hydrogenosome.[14]

NADH-coenzyme Q oxidoreductase (complex I)

 

NADH-coenzyme Q oxidoreductase, also known as NADH dehydrogenase or complex I, is the first protein in the electron transport chain.[15] Complex I is a giant kilodaltons (kDa).[16] The structure is known in detail only from a bacterium [17]; in most organisms the complex resembles a boot with a large “ball” poking out from the membrane into the mitochondrion.[18][19] The genes that encode the individual proteins are contained in both the cell nucleus and the mitochondrial genome, as is the case for many enzymes present in the mitochondrion.

The reaction which is catalyzed by this enzyme is the two electron reduction by quinone that is found in the mitochondrion membrane:

  \mbox{NADH + Q + 5H}^{+}_{matrix} \rightarrow \mbox{NAD}^+ + \mbox{QH}_2 + \mbox{4H}^+_{cytosol}

The start of the reaction, and indeed of the entire electron chain, is the binding of a NADH molecule to complex I and the donation of two electrons. The electrons enter complex I via a prosthetic group attached to the complex, iron–sulfur clusters: the second kind of prosthetic group present in the complex.[20] There are both [2Fe–2S] and [4Fe–4S] iron–sulfur clusters in complex I.

As the electrons pass through this complex, four protons are pumped from the matrix into the intermembrane space. Exactly how this occurs is unclear, but it seems to involve conformational changes in complex I that cause the protein to bind protons on the N-side of the membrane and then move them onto the P-side of the membrane.[21] Finally, the electrons are transferred from the chain of iron–sulfur clusters to a ubiquinone molecule in the membrane.[15] Reduction of ubiquinone also contributes to the generation of a proton gradient, as two protons are taken up from the matrix as it is reduced to ubiquinol (QH2).

 

Succinate-Q oxidoreductase (complex II)

fumarate and reduces ubiquinone. As this reaction releases less energy than the oxidation of NADH, complex II does not transport protons across the membrane and does not contribute to the proton gradient.

  \mbox{Succinate} + \mbox{Q} \rightarrow \mbox{Fumarate} + \mbox{QH}_2 \,

In some eukaryotes, such as the parasitic worm Ascaris suum, an enzyme similar to complex II, fumarate reductase (menaquinol:fumarate oxidoreductase, or QFR) operates in reverse to oxidize ubiquinol and reduce fumarate. This allows the worm to survive in the anaerobic environment of the large intestine, carrying out anaerobic oxidative phosphorylation with fumarate as the electron acceptor.[25] Another unconventional function of complex II is seen in the malaria parasite Plasmodium falciparum. Here, the reversed action of complex II as an oxidase is important in regenerating ubiquinol, which the parasite uses in an unusual form of pyrimidine biosynthesis.[26]

Electron transfer flavoprotein-Q oxidoreductase

Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-Q oxidoreductase), also known as electron transferring-flavoprotein dehydrogenase, is a third entry point to the electron transport chain. It is an enzyme that accepts electrons from electron-transferring flavoprotein in the mitochondrial matrix, and uses these electrons to reduce ubiquinone.[27] This enzyme contains a flavin and a [4Fe–4S] cluster, but unlike the other respiratory complexes, it attaches to the surface of the membrane and does not cross the lipid bilayer.[28]

  \mbox{ETF}_{red} + \mbox{Q} \rightarrow \mbox{ETF}_{ox} + \mbox{QH}_2 \,

In mammals, this metabolic pathway is important in acetyl-CoA dehydrogenases.[29][30] In plants, ETF-Q oxidoreductase is also important in the metabolic responses that allow survival in extended periods of darkness.[31]

 

Q-cytochrome c oxidoreductase (complex III)

heme group. The iron atoms inside complex III’s heme groups alternate between a reduced ferrous (+2) and oxidized ferric (+3) state as the electrons are transferred through the protein.

The reaction catalyzed by complex III is the oxidation of one molecule of ubiquinol and the reduction of two molecules of cytochrome c, a heme protein loosely associated with the mitochondrion. Unlike coenzyme Q, which carries two electrons, cytochrome c carries only one electron.

  \mbox{QH}_2 + \mbox{2Cyt c}_{ox} + \mbox{2H}^+_{matrix} \rightarrow \mbox{Q} + \mbox{2Cyt c}_{red} + \mbox{4H}^+_{cytosol} \,

As only one of the electrons can be transferred from the QH2 donor to a cytochrome c acceptor at a time, the reaction mechanism of complex III is more elaborate than those of the other respiratory complexes, and occurs in two steps called the Q cycle.[35] In the first step, the enzyme binds three substrates, first, QH2, which is then oxidized, with one electron being passed to the second substrate, cytochrome c. The two protons released from QH2 pass into the intermembrane space. The third substrate is Q, which accepts the second electron from the QH2 and is reduced to Q.-, which is the ubisemiquinone free-radical. The first two substrates are released, but this ubisemiquinone intermediate remains bound. In the second step, a second molecule of QH2 is bound and again passes its first electron to a cytochrome c acceptor. The second electron is passed to the bound ubisemiquinone, reducing it to QH2 as it gains two protons from the mitochondrial matrix. This QH2 is then released from the enzyme.[36]

As coenzyme Q is reduced to ubiquinol on the inner side of the membrane and oxidized to ubiquinone on the other, this causes the net transfer of protons across the membrane, adding to the proton gradient.[3] The rather complex two-step mechanism by which this occurs is important as it increases the efficiency of proton transfer. If instead of the Q cycle, one molecule of QH2 was used to directly reduce two molecules of cytochrome c, the efficiency would be halved, with only one proton transferred per cytochrome c reduced.[3]

 

Cytochrome c oxidase (complex IV)

zinc.[38]

This enzyme mediates the final reaction in the electron transport chain and transfers electrons to oxygen, while pumping protons across the membrane.[39] The final electron acceptor oxygen, which is also called the terminal electron acceptor, is reduced to water in this step. Both the direct pumping of protons and the consumption of matrix protons in the reduction of oxygen contribute to the proton gradient. The reaction catalyzed is the oxidation of cytochrome c and the reduction of oxygen:

  \mbox{4Cyt c}_{red} + \mbox{O}_{2} + \mbox{8H}^+_{matrix} \rightarrow \mbox{4Cyt c}_{ox} + \mbox{2H}_2\mbox{O} + \mbox{4H}^+_{cytosol} \,

For a detailed discussion of the mechanism of reduction of oxygen, and a better figure illustrating the redox centers in the protein, see the linked article Cytochrome c oxidase.

Alternative reductases and oxidases

Many eukaryotic organisms have electron transport chains that differ from the well-studied mammalian enzymes described above. For example, in plants, alternative NADH oxidases exist that oxidize NADH in the cytosol, rather than the mitochondrial matrix, and pass these electrons to the ubiquinone pool.[40] These enzymes do not transport protons and therefore reduce ubiquinone without altering the electrochemical gradient across the inner membrane.[41]

Another example of a divergent electron transport chain is the alternative oxidase, which is found in plants, as well as some fungi, protists, and possibly some animals.[42][43] This enzyme transfers electrons directly from ubiquinol to oxygen.[44]

The electron transport pathways produced by these alternative NADH and ubiquinone oxidases have lower oxidative stress.[47]

Organization of complexes

The original model for how the respiratory chain complexes are organized was that they diffuse freely and independently in the mitochondrial membrane.[16] However, recent data suggest that the complexes might form higher-order structures called supercomplexes or "respirasomes".[48] In this model, the various complexes exist as organized sets of interacting enzymes.[49] These associations might allow channeling of substrates between the various enzyme complexes, increasing the rate and efficiency of electron transfer.[50] Within such mammalian supercomplexes, some components would be present in higher amounts than others, with a ratio between complexes I/II/III/IV and the ATP synthase of approximately 1:1:3:7:4.[51] However, the debate over this supercomplex model is not completely resolved, as some data do not appear to fit with this model.[52][16]

Prokaryotic electron transport chains

Further information: Microbial metabolism

In contrast to the general similarity in structure and function of the electron transport chains in eukaryotes, bacteria and archaea possess a large variety of electron-transfer enzymes. These use an equally wide set of chemicals as substrates.[53] In common with eukaryotes, prokaryotic electron transport uses the energy released from the oxidation of a substrate to pump ions across a membrane and generate an electrochemical gradient. In the bacteria, oxidative phosphorylation in Escherichia coli is understood in most detail, while archaeal systems are at present poorly-understood.[54]

The main difference between eukaryotic and prokaryotic oxidative phosphorylation is that bacteria and archaea use many different substances to donate or accept electrons. This allows prokaryotes to grow under a wide variety of environmental conditions.[55] In E. coli, for example, oxidative phosphorylation can be driven by a large number of pairs of reducing agents and oxidizing agents, which are listed below. The midpoint potential of a chemical measures how much energy is released when it is oxidized or reduced, with reducing agents having negative potentials and oxidizing agents positive potentials.

Respiratory enzymes and substrates in E. coli [56]
Respiratory enzyme Redox pair  Midpoint potential 

(Volts)

 Formate dehydrogenase Bicarbonate / Formate −0.43
 Hydrogenase Hydrogen −0.42
 NADH dehydrogenase NADH −0.32
 Glycerol-3-phosphate dehydrogenase Gly-3-P −0.19
 Pyruvate oxidase  Pyruvate    ?
 Lactate dehydrogenase Lactate −0.19
 D-amino acid dehydrogenase  2-oxoacid + D-amino acid    ?
 Glucose oxidase Gluconate −0.14
 Succinate dehydrogenase Fumarate +0.03
 Ubiquinol oxidase Oxygen / Water +0.82
 Nitrate reductase Nitrite +0.42
 Nitrite reductase Ammonia +0.36
 Dimethyl sulfoxide reductase DMS +0.16
 Trimethylamine N-oxide reductase TMAO / TMA +0.13
 Fumarate reductase Succinate +0.03

As shown above, E. coli can grow with reducing agents such as formate, hydrogen or lactate as electron donors, and nitrate, DMSO or oxygen as acceptors.[55] The larger the difference in midpoint potential between an oxidizing and reducing agent, the more energy is released when they react. Out of these compounds, the succinate/fumarate pair is unusual, as its midpoint potential is close to zero. Succinate can therefore be oxidized to fumarate if a strong oxidizing agent such as oxygen is available, or fumarate can be reduced to succinate using a strong reducing agent such as formate. These alternative reactions are catalyzed by fumarate reductase, respectively.[57]

Some prokaryotes use redox pairs that have only a small difference in midpoint potential. For example, anabolism.[58] This problem is solved by using a nitrite oxidoreductase to produce enough proton-motive force to run part of the electron transport chain in reverse, causing complex I to generate NADH.[59][60]

Prokaryotes control their use of these electron donors and acceptors by varying which enzymes are produced, in response to environmental conditions.[61] This flexibility is possible because different oxidases and reductases use the same ubiquinone pool. This allows many combinations of enzymes to function together, linked by the common ubiquinol intermediate.[56] These respiratory chains therefore have a modular design, with easily interchangeable sets of enzyme systems.

In addition to this metabolic diversity, prokaryotes also possess a range of isozymes – different enzymes that catalyze the same reaction. For example, in E. coli there are two different types of ubiquinol oxidase using oxygen as an electron acceptor. Under highly-aerobic conditions, the cell uses an oxidase with a low affinity for oxygen that can transport two protons per electron. However, if levels of oxygen fall, they switch to an oxidase that only transfers one proton per electron, but has a high affinity for oxygen.[62]

ATP synthase

Further information: ATP synthase

 

ATP synthase, also called complex V, is the final enzyme in the oxidative phosphorylation pathway. This enzyme is found in all forms of life and functions in the same way in both prokaryotes or eukaryotes.[63] The enzyme uses the energy stored in a proton gradient across a membrane to drive the synthesis of ATP from ADP and phosphate (Pi). Estimates of the number of protons required to synthesise one ATP have ranged from three to four,[64][65] with some suggesting cells can vary this ratio, to suit different conditions.[66]

  \mbox{ADP} + \mbox{P}_{i} + \mbox{4H}^+_{cytosol} \rightleftharpoons \mbox{ATP} + \mbox{H}_{2}\mbox{O} + \mbox{4H}^+_{matrix}

This vacuolar type H+-ATPases the same reaction is used to acidify cellular compartments, by pumping protons and hydrolysing ATP.[67]

ATP synthase is a massive protein complex with a mushroom-like shape. The mammalian enzyme complex contains 16 subunits and has a mass of approximately 600 kilodaltons.[68] The portion embedded within the membrane is called FO and contains a ring of c subunits and the proton channel. The stalk and the ball-shaped headpiece is called F1 and is the site of ATP synthesis. The ball-shaped complex at the end of the F1 portion contains six proteins of two different kinds (three α subunits and three β subunits), whereas the "stalk" consists of one protein: the γ subunit, with the tip of the stalk extending into the ball of α and β subunits.[69] Both the α and β subunits bind nucleotides, but only the β subunits catalyze the ATP synthesis reaction. Reaching along the side of the F1 portion and back into the membrane is a long rod-like subunit that anchors the α and β subunits into the base of the enzyme.

As protons cross the membrane through the channel in the base of ATP synthase this causes the FO proton-driven motor to rotate.[70] Rotation might be caused by changes in the ionization of amino acids in the ring of c subunits causing electrostatic interactions that propel the ring of c subunits past the proton channel.[71] This rotating ring in turn drives the rotation of the central axle (the γ subunit stalk) within the α and β subunits. The α and β subunits are prevented from rotating themselves by the side-arm, which acts as a stator. This movement of the tip of the γ subunit within the ball of α and β subunits provides the energy for the active sites in the β subunits to undergo a cycle of movements that produces and then releases ATP.[2]   This ATP synthesis reaction is called the binding change mechanism and involves the active site of a β subunit cycling between three states.[72] In the "open" state, ADP and phosphate enter the active site (shown in brown in the diagram). The protein then closes up around the molecules and binds them loosely – the "loose" state (shown in red). The enzyme then changes shape again and forces these molecules together, with the active site in the resulting "tight" state (shown in pink) binding the newly-produced ATP molecule with very high affinity. Finally, the active site cycles back to the open state, releasing ATP and binding more ADP and phosphate, ready for the next cycle.

In some bacteria and archaea, ATP synthesis is driven by the movement of sodium ions through the cell membrane, rather than the movement of protons.[73][74] Archaea such as Methanococcus also contain the A1Ao synthase, a form of the enzyme that contains additional proteins with little similarity in sequence to other bacterial and eukaryotic ATP synthase subunits. It is possible that in some species the A1Ao form of the enzyme is a specialized sodium-driven ATP synthase,[75] but this might not be true in all cases.[74]

Reactive oxygen species

Further information: Antioxidant

Molecular oxygen is an ideal terminal peroxide.

\begin{matrix} \quad & {e^-} & \quad & {e^-} \\ {\mbox{O}_{2}} & \longrightarrow & \mbox{O}_2^{\underline{\bullet}} & \longrightarrow & \mbox{O}_2^{2-} \\ \quad & \quad & \mbox{Superoxide} & \quad & \mbox{Peroxide} \\ \quad & \quad \end{matrix}

These DNA. This cellular damage might contribute to disease and is proposed as one cause of ageing.[77][78]

The cytochrome c oxidase complex is highly efficient at reducing oxygen to water, and it releases very few partly-reduced intermediates; however small amounts of superoxide anion and peroxide are produced by the electron transport chain.[79] Particularly important is the reduction of coenzyme Q in complex III, as a highly reactive ubisemiquinone free radical is formed as an intermediate in the Q cycle. This unstable species can lead to electron "leakage" when electrons transfer directly to oxygen, forming superoxide.[80]

To counteract these reactive oxygen species, cells contain numerous peroxidases,[76]which detoxify the reactive species, limiting damage to the cell.

Inhibitors

There are several well-known oligomycin inhibits ATP synthase, protons cannot pass back into the mitochondrion.[81] As a result, the proton pumps are unable to operate, as the gradient becomes too strong for them to overcome. NADH is then no longer oxidized and the citric acid cycle ceases to operate because the concentration of NAD+ falls below the concentration that these enzymes can use.

Compounds Use Effect on oxidative phosphorylation
Carbon monoxide Poisons Inhibit the electron transport chain by binding more strongly than oxygen to the Cu center in cytochrome c oxidase, preventing the reduction of oxygen.[82]
Oligomycin Antibiotic Inhibits ATP synthase by blocking the flow of protons through the Fo subunit.[81]
CCCP
2,4-Dinitrophenol 		Poisons Ionophores that disrupt the proton gradient by carrying protons across the membrane. This uncouples proton pumping from ATP synthesis.[83]
Rotenone Pesticide Prevents the transfer of electrons from complex I to ubiquinone by blocking to the ubiquinone-binding site.[84]

Not all inhibitors of oxidative phosphorylation are toxins. In brown adipose tissue, regulated proton channels called uncoupling proteins can uncouple respiration from ATP synthesis.[85] This rapid respiration produces heat, and is particularly important as a way of maintaining body temperature for hibernating animals, although these proteins may also have a more general function in cells' responses to stress.[86]

History

Further information: History of molecular biology

The field of oxidative phosphorylation began with the report in 1906 by Arthur Harden of a vital role for phosphate in cellular fermentation, but initially only sugar phosphates were known to be involved.[87] However, in the early 1940s, the link between the oxidation of sugars and the generation of ATP was firmly established by Herman Kalckar,[88] confirming the central role of ATP in energy transfer that had been proposed by Fritz Albert Lipmann in 1941.[89] Later, in 1949, Morris Friedkin and Albert L. Lehninger proved that the coenzyme NADH linked metabolic pathways such as the citric acid cycle and the synthesis of ATP.[90]

For another twenty years, the mechanism by which ATP is generated remained mysterious, with scientists searching for an elusive "high-energy intermediate" that would link oxidation and phosphorylation reactions.[91] This puzzle was solved by John E. Walker, with Walker and Boyer being awarded a Nobel prize in 1997.[97]

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Further reading

Introductory

  • Nelson DL; Cox MM (2004). Lehninger Principles of Biochemistry, 4th ed, W. H. Freeman. ISBN 0-716-74339-6. 
  • Schneider ED; Sagan D (2006). Into the Cool: Energy Flow, Thermodynamics and Life, 1st ed, University of Chicago Press. ISBN 0-226-73937-6. 

Advanced

  • Nicholls DG; Ferguson SJ (2002). Bioenergetics 3, 1st ed, Academic Press. ISBN 0-125-18121-3. 
  • Haynie D (2001). Biological Thermodynamics, 1st ed, Cambridge University Press. ISBN 0-521-79549-4. 
  • Rajan SS (2003). Introduction to Bioenergetics, 1st ed, Anmol. ISBN 8-126-11364-2. 
  • Wikstrom M (Ed) (2005). Biophysical and Structural Aspects of Bioenergetics, 1st ed, Royal Society of Chemistry. ISBN 0-854-04346-2. 

Structural resources

  • Animations of the ATP synthase Hongyun Wang and George Oster, University of California, Berkeley
  • PDB molecule of the month:
    • ATP synthase
    • Cytochrome c
    • Cytochrome c oxidase
  • Interactive molecular models at Universidade Fernando Pessoa:
    • NADH dehydrogenase
    • succinate dehydrogenase
    • Coenzyme Q - cytochrome c reductase
    • cytochrome c oxidase
v • d • e
Mitochondrial Alternative oxidase - Electron-transferring-flavoprotein dehydrogenase
v • d • e
Ethanol Formation
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Oxidative_phosphorylation". A list of authors is available in Wikipedia.