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| [[File:Mitochondrial electron transport chain—Etc4.svg|thumb|400px|The [[electron transport chain]] in the [[mitochondrion]] is the site of oxidative phosphorylation in [[eukaryote]]s. The NADH and succinate generated in the [[citric acid cycle]] are oxidized, releasing energy to power the [[ATP synthase]].]]
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| '''Oxidative phosphorylation''' (or OXPHOS in short) is the [[metabolic pathway]] in which the [[mitochondria]] in [[Cell (biology)|cell]]s use their structure, [[enzyme]]s, and [[energy]] released by the [[redox|oxidation]] of [[nutrient]]s to reform [[Adenosine_triphosphate|ATP]]. Although the many forms of life on earth use a range of different nutrients, ATP is the molecule that supplies energy to [[metabolism]]. Almost all [[aerobic organism]]s carry out oxidative phosphorylation. This pathway is probably so pervasive because it is a highly efficient way of releasing energy, compared to alternative [[fermentation (biochemistry)|fermentation]] processes such as anaerobic [[glycolysis]].
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| During oxidative phosphorylation, electrons are transferred from [[reducing agent|electron donors]] to [[oxidizing agent|electron acceptors]] such as [[oxygen]], in [[redox reaction]]s. These redox reactions release energy, which is used to form ATP. In [[eukaryote]]s, these redox reactions are carried out by a series of [[protein complex]]es within the cell's intermembrane wall [[mitochondrion|mitochondria]], whereas, in [[prokaryote]]s, these proteins are located in the cells' intermembrane space. These linked sets of proteins are called [[electron transport chain]]s. In eukaryotes, five main protein complexes are involved, whereas in prokaryotes many different enzymes are present, using a variety of electron donors and acceptors.
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| The energy released by electrons flowing through this electron transport chain is used to transport protons across the [[inner mitochondrial membrane]], in a process called ''[[electron transport]]''. This generates [[potential energy]] in the form of a [[pH]] gradient and an [[Membrane potential|electrical potential]] across this membrane. This store of energy is tapped by allowing protons to flow back across the membrane and down this gradient, through a large [[enzyme]] called [[ATP synthase]]; this process is known as [[chemiosmosis]]. This enzyme uses this energy to generate ATP from [[adenosine diphosphate]] (ADP), in a [[phosphorylation]] reaction. This reaction is driven by the proton flow, which forces the [[rotation]] of a part of the enzyme; the ATP synthase is a rotary mechanical motor.
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| Although oxidative phosphorylation is a vital part of [[metabolism]], it produces [[reactive oxygen species]] such as [[superoxide]] and [[hydrogen peroxide]], which lead to propagation of [[Radical (chemistry)|free radicals]], damaging cells and contributing to [[disease]] and, possibly, [[aging]] ([[senescence]]). The enzymes carrying out this metabolic pathway are also the target of many drugs and poisons that [[enzyme inhibitor|inhibit]] their activities.
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| ==Overview of energy transfer by chemiosmosis==
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| {{further2|[[Chemiosmosis]] and [[Bioenergetics]]}}
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| 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 [[NADH]] to [[electron acceptor]]s such as [[oxygen]], is an [[exergonic]] process – it releases energy, whereas the synthesis of ATP is an [[endergonic]] process, which 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 ''[[chemiosmosis]]''.<ref>{{cite journal |author=Mitchell P, Moyle J |title=Chemiosmotic hypothesis of oxidative phosphorylation |journal=Nature |volume=213 |issue=5072 |pages=137–9 |year=1967 |pmid=4291593 |doi=10.1038/213137a0|bibcode = 1967Natur.213..137M }}</ref> In practice, this is like a simple [[Electrical network|electric circuit]], with a current of protons being driven from the negative N-side of the membrane to the positive P-side by the proton-pumping enzymes of the electron transport chain. These enzymes are like a [[battery (electricity)|battery]], as they perform [[Work (thermodynamics)|work]] to drive current through the circuit. The movement of protons creates an [[electrochemical gradient]] across the membrane, which is often called the ''proton-motive force''. It has two components: a difference in proton concentration (a H+ gradient, ΔpH) and a difference in [[electric potential]], with the N-side having a negative charge.<ref name=Dimroth>{{cite journal |author=Dimroth P, Kaim G, Matthey U |title=Crucial role of the membrane potential for ATP synthesis by F(1)F(o) ATP synthases |journal=J. Exp. Biol. |volume=203 |issue=Pt 1 |pages=51–9 |date=1 January 2000|pmid=10600673 |url=http://jeb.biologists.org/cgi/reprint/203/1/51}}</ref>
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| 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.<ref name=Schultz>{{cite journal |author=Schultz B, Chan S |title=Structures and proton-pumping strategies of mitochondrial respiratory enzymes |journal=Annu Rev Biophys Biomol Struct |volume=30|pages=23–65 |year=2001 |pmid=11340051 |doi=10.1146/annurev.biophys.30.1.23}}</ref> This kinetic energy drives the rotation of part of the enzymes structure and couples this motion to the synthesis of ATP.
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| The two components of the proton-motive force are [[thermodynamic]]ally equivalent: In mitochondria, the largest part of energy is provided by the potential; in [[alkaliphile]] bacteria the electrical energy even has to compensate for a counteracting inverse pH difference. Inversely, [[chloroplast]]s operate mainly on ΔpH. However, they also require a small membrane potential for the kinetics of ATP synthesis. At least in the case of the [[Fusobacteria|fusobacterium]] ''P. modestum'' it drives the counter-rotation of subunits a and c of the F<sub>O</sub> motor of ATP synthase.<ref name=Dimroth />
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| The amount of energy released by oxidative phosphorylation is high, compared with the amount produced by [[anaerobic fermentation]]. [[Glycolysis]] produces only 2 ATP molecules, but somewhere between 30 and 36 ATPs are produced by the oxidative phosphorylation of the 10 NADH and 2 succinate molecules made by converting one molecule of [[glucose]] to carbon dioxide and water,<ref>{{cite journal |author=Rich PR |title=The molecular machinery of Keilin's respiratory chain |journal=Biochem. Soc. Trans. |volume=31 |issue=Pt 6 |pages=1095–105 |year=2003 |pmid=14641005 |url=http://www.biochemsoctrans.org/bst/031/1095/bst0311095.htm |doi=10.1042/BST0311095}}</ref> while each cycle of [[beta oxidation]] of a [[fatty acid]] yields about 14 ATPs. These ATP yields are theoretical maximum values; in practice, some protons leak across the membrane, lowering the yield of ATP.<ref>{{cite journal |author=Porter RK, Brand MD |title=Mitochondrial proton conductance and H+/O ratio are independent of electron transport rate in isolated hepatocytes |journal=Biochem. J. |volume=310 |issue=(Pt 2) |pages=379–82 |year=1995 |pmid=7654171 |pmc=1135905}}</ref>
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| ==Electron and proton transfer molecules==
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| {{further2|[[Coenzyme]] and [[Cofactor (biochemistry)|Cofactor]]}}
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| [[File:Ubiquinone–ubiquinol conversion.svg|thumb|250px|left|Reduction of [[coenzyme Q]] from its [[ubiquinone]] form (Q) to the reduced ubiquinol form (QH<sub>2</sub>).]]
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| 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-[[soluble]] electron transfer protein [[cytochrome c]].<ref>{{cite journal |author=Mathews FS |title=The structure, function and evolution of cytochromes |journal=Prog. Biophys. Mol. Biol. |volume=45 |issue=1 |pages=1–56 |year=1985 |pmid=3881803 |doi=10.1016/0079-6107(85)90004-5}}</ref> This carries only electrons, and these are transferred by the reduction and oxidation of an [[iron]] atom that the protein holds within a [[heme]] group in its structure. Cytochrome c is also found in some bacteria, where it is located within the [[periplasmic space]].<ref>{{cite journal |author=Wood PM |title=Why do c-type cytochromes exist? |journal=FEBS Lett. |volume=164 |issue=2 |pages=223–6 |year=1983 |pmid=6317447 |doi=10.1016/0014-5793(83)80289-0}}</ref>
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| Within the inner mitochondrial membrane, the [[lipid]]-soluble electron carrier [[coenzyme Q10]] (Q) carries both electrons and protons by a [[redox]] cycle.<ref>{{cite journal |author=Crane FL |title=Biochemical functions of coenzyme Q10 |journal=Journal of the American College of Nutrition |volume=20 |issue=6 |pages=591–8 |date=1 December 2001|pmid=11771674 |url=http://www.jacn.org/cgi/content/full/20/6/591}}</ref> This small [[1,4-Benzoquinone|benzoquinone]] molecule is very [[hydrophobe|hydrophobic]], so it diffuses freely within the membrane. When Q accepts two electrons and two protons, it becomes reduced to the ''[[Hydroquinone|ubiquinol]]'' form (QH<sub>2</sub>); when QH<sub>2</sub> releases two electrons and two protons, it becomes oxidized back to the ''ubiquinone'' (Q) form. As a result, if two enzymes are arranged so that Q is reduced on one side of the membrane and QH<sub>2</sub> oxidized on the other, ubiquinone will couple these reactions and shuttle protons across the membrane.<ref>{{cite journal |author=Mitchell P |title=Keilin's respiratory chain concept and its chemiosmotic consequences |journal=Science |volume=206 |issue=4423 |pages=1148–59 |year=1979 |pmid=388618 |doi=10.1126/science.388618|bibcode = 1979Sci...206.1148M }}</ref> Some bacterial electron transport chains use different quinones, such as [[vitamin K|menaquinone]], in addition to ubiquinone.<ref name=Søballe>{{cite journal |author=Søballe B, Poole RK |title=Microbial ubiquinones: multiple roles in respiration, gene regulation and oxidative stress management |journal=Microbiology (Reading, Engl.) |volume=145 |pages=1817–30 |year=1999 |pmid=10463148 |url=http://mic.sgmjournals.org/cgi/reprint/145/8/1817.pdf|format=PDF |issue=8}}</ref>
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| Within proteins, electrons are transferred between [[Flavin group|flavin]] cofactors,<ref name=Schultz/><ref name=Johnson>{{cite journal |author=Johnson D, Dean D, Smith A, Johnson M |title=Structure, function, and formation of biological iron-sulfur clusters |journal=Annu Rev Biochem |volume=74 |pages=247–81 |year=2005 |pmid=15952888 |doi=10.1146/annurev.biochem.74.082803.133518}}</ref> iron–sulfur clusters, and cytochromes. There are several types of iron–sulfur cluster. The simplest kind found in the electron transfer chain consists of two iron atoms joined by two atoms of inorganic [[sulfur]]; these are called [2Fe–2S] clusters. The second kind, called [4Fe–4S], contains a cube of four iron atoms and four sulfur atoms. Each iron atom in these clusters is coordinated by an additional [[amino acid]], usually by the sulfur atom of [[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 quite long distances through proteins by hopping along chains of these cofactors.<ref>{{cite journal |author=Page CC, Moser CC, Chen X, Dutton PL |title=Natural engineering principles of electron tunnelling in biological oxidation-reduction |journal=Nature |volume=402 |issue=6757 |pages=47–52 |year=1999 |pmid=10573417 |doi=10.1038/46972|bibcode = 1999Natur.402...47P }}</ref> This occurs by [[quantum tunnelling]], which is rapid over distances of less than 1.4{{e|−9}} m.<ref>{{cite journal |author=Leys D, Scrutton NS |title=Electrical circuitry in biology: emerging principles from protein structure |journal=Current Opinion in Structural Biology |volume=14 |issue=6 |pages=642–7 |year=2004 |pmid=15582386 |doi=10.1016/j.sbi.2004.10.002}}</ref>
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| ==Eukaryotic electron transport chains==
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| {{further2|[[Electron transport chain]] and [[Chemiosmosis]]}}
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| Many [[catabolic]] biochemical processes, such as [[glycolysis]], the [[citric acid cycle]], and [[beta oxidation]], produce the reduced [[coenzyme]] NADH. This coenzyme contains electrons that have a high [[Standard electrode potential|transfer potential]]; in other words, they will release a large amount of energy upon oxidation. However, the cell does not release this energy all at once, as this would be an uncontrollable reaction. Instead, the electrons are removed from NADH and passed to oxygen through a series of enzymes that each release a small amount of the energy. This set of enzymes, consisting of complexes I through IV, is called the electron transport chain and is found in the inner membrane of the mitochondrion. [[succinic acid|Succinate]] is also oxidized by the electron transport chain, but feeds into the pathway at a different point.
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| In [[eukaryote]]s, the enzymes in this electron transport system use the energy released from the oxidation of NADH to pump [[proton]]s across the inner membrane of the mitochondrion. This causes protons to build up in the [[intermembrane space]], and generates an [[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]].<ref>{{cite journal |author=Boxma B, de Graaf RM, van der Staay GW, ''et al.'' |title=An anaerobic mitochondrion that produces hydrogen |journal=Nature |volume=434 |issue=7029 |pages=74–9 |year=2005 |pmid=15744302 |doi=10.1038/nature03343|bibcode = 2005Natur.434...74B }}</ref>
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| {| class="wikitable" style="margin-left: auto; margin-right: auto; text-align:center"
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| |+ Typical respiratory enzymes and substrates in eukaryotes.
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| |-
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| !Respiratory enzyme
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| ![[redox|Redox pair]]
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| ! [[Standard electrode potential#Non-standard condition|Midpoint potential]]
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| (Volts)
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| |-
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| | [[NADH dehydrogenase]]
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| | [[Nicotinamide adenine dinucleotide|NAD<sup>+</sup>]] / [[Nicotinamide adenine dinucleotide|NADH]]
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| | −0.32<ref name=Pedersen>Medical CHEMISTRY Compendium. By Anders Overgaard Pedersen and Henning Nielsen. Aarhus University. 2008</ref>
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| |-
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| | [[Succinate dehydrogenase]]
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| | [[Flavin mononucleotide|FMN]] or [[FAD]] / FMNH<sub>2</sub> or FADH<sub>2</sub>
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| | −0.20<ref name=Pedersen/>
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| |-
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| | [[Coenzyme Q - cytochrome c reductase|Cytochrome bc<sub>1</sub> complex]]
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| | [[Coenzyme Q10]]<sub>ox</sub> / Coenzyme Q10<sub>red</sub>
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| | +0.06<ref name=Pedersen/>
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| |-
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| | Cytochrome bc<sub>1</sub> complex
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| | [[Cytochrome b]]<sub>ox</sub> / Cytochrome b<sub>red</sub>
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| | +0.12<ref name=Pedersen/>
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| |-
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| |align=left|[[Cytochrome c oxidase|Complex IV]]
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| | [[Cytochrome c]]<sub>ox</sub> / Cytochrome c<sub>red</sub>
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| | +0.22<ref name=Pedersen/>
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| |-
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| |align=left|Complex IV
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| | [[Cytochrome a]]<sub>ox</sub> / Cytochrome a<sub>red</sub>
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| | +0.29<ref name=Pedersen/>
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| |-
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| |align=left|Complex IV
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| | O<sub>2</sub> / HO<sup>−</sup>
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| | +0.82<ref name=Pedersen/>
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| |-
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| |align=left colspan=3|<span style="font-size:87%;"> Conditions: pH = 7<ref name=Pedersen/>
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| |}
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| ===NADH-coenzyme Q oxidoreductase (complex I)===
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| [[File:Complex I.svg|350px|thumb|right|Complex I or [[NADH dehydrogenase|NADH-Q oxidoreductase]]. The abbreviations are discussed in the text. In all diagrams of respiratory complexes in this article, the matrix is at the bottom, with the intermembrane space above.]]
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| [[NADH dehydrogenase|NADH-coenzyme Q oxidoreductase]], also known as ''NADH dehydrogenase'' or ''complex I'', is the first protein in the electron transport chain.<ref name=Hirst>{{cite journal |author=Hirst J |title=Energy transduction by respiratory complex I—an evaluation of current knowledge |journal=Biochem. Soc. Trans. |volume=33 |issue=Pt 3 |pages=525–9 |year=2005 |pmid=15916556 |url=http://www.biochemsoctrans.org/bst/033/0525/0330525.pdf |format=PDF|doi=10.1042/BST0330525}}</ref> Complex I is a giant [[enzyme]] with the mammalian complex I having 46 subunits and a molecular mass of about 1,000 [[atomic mass unit|kilodaltons]] (kDa).<ref name=Lenaz>{{cite journal |author=Lenaz G, Fato R, Genova M, Bergamini C, Bianchi C, Biondi A |title=Mitochondrial Complex I: structural and functional aspects |journal=Biochim Biophys Acta |volume=1757 |issue=9–10 |pages=1406–20 |year=2006 |pmid=16828051 |doi=10.1016/j.bbabio.2006.05.007}}</ref> The structure is known in detail only from a bacterium;<ref name="thermophilus1">{{cite journal | doi = 10.1126/science.1123809 | last1 = Sazanov | first1 = L.A. | last2 = Hinchliffe | first2 = P. | author-separator =, | author-name-separator= | year = 2006 | title = Structure of the hydrophilic domain of respiratory complex I from Thermus thermophilus | url = | journal = Science | volume = 311 | issue = 5766| pages = 1430–1436 | pmid = 16469879 |bibcode = 2006Sci...311.1430S }}</ref><ref name=Ecoli>Efremov R.G., Baradaran R., & Sazanov L.A., (2010) The arcdhitecture of respiratory complex I, Nature 465, 441-445</ref> in most organisms the complex resembles a boot with a large "ball" poking out from the membrane into the mitochondrion.<ref>{{cite journal |author=Baranova EA, Holt PJ, Sazanov LA |title=Projection structure of the membrane domain of Escherichia coli respiratory complex I at 8 A resolution |journal=J. Mol. Biol. |volume=366 |issue=1 |pages=140–54 |year=2007 |pmid=17157874 |doi=10.1016/j.jmb.2006.11.026}}</ref><ref>{{cite journal |author=Friedrich T, Böttcher B |title=The gross structure of the respiratory complex I: a Lego System |journal=Biochim. Biophys. Acta |volume=1608 |issue=1 |pages=1–9 |year=2004 |pmid=14741580 |doi=10.1016/j.bbabio.2003.10.002}}</ref> 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.
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| The reaction that is catalyzed by this enzyme is the two electron oxidation of [[Nicotinamide adenine dinucleotide|NADH]] by [[coenzyme Q10]] or ''ubiquinone'' (represented as Q in the equation below), a lipid-soluble [[quinone]] that is found in the mitochondrion membrane:
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| <math>\rm NADH + Q + 5\; H^{+}_{matrix} \rightarrow NAD^+ + QH_2 + 4\; H^+_{intermembrane} \!</math>
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| 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, [[flavin mononucleotide]] (FMN). The addition of electrons to FMN converts it to its reduced form, FMNH<sub>2</sub>. The electrons are then transferred through a series of [[iron-sulfur cluster|iron–sulfur clusters]]: the second kind of prosthetic group present in the complex.<ref name="thermophilus1"/> There are both [2Fe–2S] and [4Fe–4S] iron–sulfur clusters in complex I.
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| 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 change]]s in complex I that cause the protein to bind protons on the N-side of the membrane and release them on the P-side of the membrane.<ref>{{cite journal |author=Hirst J |title=Towards the molecular mechanism of respiratory complex I |journal=Biochem. J. |volume=425 |issue=2 |pages=327–39 |date=January 2010 |pmid=20025615 |doi=10.1042/BJ20091382}}</ref> Finally, the electrons are transferred from the chain of iron–sulfur clusters to a ubiquinone molecule in the membrane.<ref name=Hirst/> 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]] (QH<sub>2</sub>).
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| ===Succinate-Q oxidoreductase (complex II)===
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| [[File:Complex II.svg|250px|thumb|right|Complex II: [[Succinate - coenzyme Q reductase|Succinate-Q oxidoreductase]].]]
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| [[Succinate - coenzyme Q reductase|Succinate-Q oxidoreductase]], also known as ''complex II'' or ''succinate dehydrogenase'', is a second entry point to the electron transport chain.<ref>{{cite journal |author=Cecchini G |title=Function and structure of complex II of the respiratory chain |journal=Annu Rev Biochem |volume=72 |pages=77–109 |year=2003 |pmid=14527321 |doi=10.1146/annurev.biochem.72.121801.161700}}</ref> It is unusual because it is the only enzyme that is part of both the citric acid cycle and the electron transport chain. Complex II consists of four protein subunits and contains a bound [[FAD|flavin adenine dinucleotide]] (FAD) cofactor, iron–sulfur clusters, and a [[heme]] group that does not participate in electron transfer to coenzyme Q, but is believed to be important in decreasing production of reactive oxygen species.<ref>{{cite journal | doi = 10.1126/science.1079605 | last1 = Yankovskaya | first1 = V. | last2 = Horsefield | first2 = R. | last3 = Tornroth | first3 = S. | last4 = Luna-Chavez | first4 = C. | last5 = Miyoshi | first5 = H. | last6 = Leger | first6 = C. | last7 = Byrne | first7 = B. | last8 = Cecchini | first8 = G. | last9 = Iwata | first9 = S. ''et al.'' | author-separator =, | author-name-separator= | year = 2003 | title = Architecture of succinate dehydrogenase and reactive oxygen species generation | url = | journal = Science | volume = 299 | issue = 5607| pages = 700–704 | pmid = 12560550 |bibcode = 2003Sci...299..700Y }}</ref><ref>{{cite journal |author=Horsefield R, Iwata S, Byrne B |title=Complex II from a structural perspective |journal=Curr. Protein Pept. Sci. |volume=5 |issue=2 |pages=107–18 |year=2004 |pmid=15078221 |doi=10.2174/1389203043486847}}</ref> It oxidizes [[succinic acid|succinate]] to [[Fumaric acid|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.
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| :<math>\rm Succinate + Q \rightarrow Fumarate + QH_2 \! </math>
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| In some eukaryotes, such as the [[parasitic worm]] ''[[Large roundworm of pigs|Ascaris suum]]'', an enzyme similar to complex II, fumarate reductase (menaquinol:fumarate
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| 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.<ref>{{cite journal |author=Kita K, Hirawake H, Miyadera H, Amino H, Takeo S |title=Role of complex II in anaerobic respiration of the parasite mitochondria from Ascaris suum and Plasmodium falciparum |journal=Biochim. Biophys. Acta |volume=1553 |issue=1–2 |pages=123–39 |year=2002 |pmid=11803022 |doi=10.1016/S0005-2728(01)00237-7}}</ref> 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.<ref>{{cite journal |author=Painter HJ, Morrisey JM, Mather MW, Vaidya AB |title=Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum |journal=Nature |volume=446 |issue=7131 |pages=88–91 |year=2007 |pmid=17330044 |doi=10.1038/nature05572|bibcode = 2007Natur.446...88P }}</ref>
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| ===Electron transfer flavoprotein-Q oxidoreductase===
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| [[Electron-transferring-flavoprotein dehydrogenase|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.<ref>{{cite journal |author=Ramsay RR, Steenkamp DJ, Husain M |title=Reactions of electron-transfer flavoprotein and electron-transfer flavoprotein: ubiquinone oxidoreductase |journal=Biochem. J. |volume=241 |issue=3 |pages=883–92 |year=1987 |pmid=3593226 |doi= |pmc=1147643}}</ref> This enzyme contains a [[Flavin group|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.<ref>{{cite journal |author=Zhang J, Frerman FE, Kim JJ |title=Structure of electron transfer flavoprotein-ubiquinone oxidoreductase and electron transfer to the mitochondrial ubiquinone pool |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=44 |pages=16212–7 |year=2006 |pmid=17050691 |doi=10.1073/pnas.0604567103 |pmc=1637562|bibcode = 2006PNAS..10316212Z }}</ref>
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| :<math>\rm ETF_{red} + Q \rightarrow ETF_{ox} + QH_2 \! </math>
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| In mammals, this metabolic pathway is important in [[beta oxidation]] of [[fatty acid]]s and catabolism of [[amino acid]]s and [[choline]], as it accepts electrons from multiple [[acetyl-CoA]] dehydrogenases.<ref>{{cite journal |author=Ikeda Y, Dabrowski C, Tanaka K |title=Separation and properties of five distinct acyl-CoA dehydrogenases from rat liver mitochondria. Identification of a new 2-methyl branched chain acyl-CoA dehydrogenase |journal=J. Biol. Chem. |volume=258 |issue=2 |pages=1066–76 |date=25 January 1983|pmid=6401712 |url=http://www.jbc.org/cgi/reprint/258/2/1066}}</ref><ref>{{cite journal |author=Ruzicka FJ, Beinert H |title=A new iron-sulfur flavoprotein of the respiratory chain. A component of the fatty acid beta oxidation pathway |journal=J. Biol. Chem. |volume=252 |issue=23 |pages=8440–5 |year=1977 |pmid=925004 |url=http://www.jbc.org/cgi/reprint/252/23/8440.pdf|format=PDF}}</ref> In plants, ETF-Q oxidoreductase is also important in the metabolic responses that allow survival in extended periods of darkness.<ref>{{cite journal |author=Ishizaki K, Larson TR, Schauer N, Fernie AR, Graham IA, Leaver CJ |title=The Critical Role of Arabidopsis Electron-Transfer Flavoprotein:Ubiquinone Oxidoreductase during Dark-Induced Starvation |journal=Plant Cell |volume=17 |issue=9 |pages=2587–600 |year=2005 |pmid=16055629 |pmc=1197437 |doi=10.1105/tpc.105.035162}}</ref>
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| ===Q-cytochrome c oxidoreductase (complex III)===
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| [[File:Complex III reaction.svg|420px|thumb|right|The two electron transfer steps in complex III: [[Coenzyme Q - cytochrome c reductase|Q-cytochrome c oxidoreductase]]. After each step, Q (in the upper part of the figure) leaves the enzyme.]]
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| [[Coenzyme Q - cytochrome c reductase|Q-cytochrome c oxidoreductase]] is also known as ''cytochrome c reductase'', ''cytochrome bc<sub>1</sub> complex'', or simply ''complex III''.<ref>{{cite journal |author=Berry E, Guergova-Kuras M, Huang L, Crofts A |title=Structure and function of cytochrome bc complexes |journal=Annu Rev Biochem |volume=69 |pages=1005–75 |year=2000 |pmid=10966481 |doi=10.1146/annurev.biochem.69.1.1005}}</ref><ref>{{cite journal |author=Crofts AR |title=The cytochrome bc1 complex: function in the context of structure |journal=Annu. Rev. Physiol. |volume=66 |pages=689–733 |year=2004 |pmid=14977419 |doi=10.1146/annurev.physiol.66.032102.150251}}</ref> In mammals, this enzyme is a [[protein dimer|dimer]], with each subunit complex containing 11 protein subunits, an [2Fe-2S] iron–sulfur cluster and three [[cytochrome]]s: one [[cytochrome]] c<sub>1</sub> and two b [[cytochromes]].<ref>{{cite journal |author=Iwata S, Lee JW, Okada K, ''et al.'' |title=Complete structure of the 11-subunit bovine mitochondrial cytochrome bc1 complex |journal=Science |volume=281 |issue=5373 |pages=64–71 |year=1998 |pmid=9651245 |doi=10.1126/science.281.5373.64|bibcode = 1998Sci...281...64I }}</ref> A cytochrome is a kind of electron-transferring protein that contains at least one [[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.
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| 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.
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| :<math>\rm QH_2 + 2\; Cyt\,c_{ox} + 2\; H^+_{matrix} \rightarrow Q + 2\; Cyt\,c_{red} + 4\; H^+_{intermembrane} \! </math>
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| As only one of the electrons can be transferred from the QH<sub>2</sub> 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]].<ref>{{cite journal |author=Trumpower BL |title=The protonmotive Q cycle. Energy transduction by coupling of proton translocation to electron transfer by the cytochrome bc1 complex |journal=J. Biol. Chem. |volume=265 |issue=20 |pages=11409–12 |year=1990 |pmid=2164001 |url=http://www.jbc.org/cgi/reprint/265/20/11409.pdf|format=PDF}}</ref> In the first step, the enzyme binds three substrates, first, QH<sub>2</sub>, which is then oxidized, with one electron being passed to the second substrate, cytochrome c. The two protons released from QH<sub>2</sub> pass into the intermembrane space. The third substrate is Q, which accepts the second electron from the QH<sub>2</sub> and is reduced to Q<sup>.-</sup>, which is the [[semiquinone|ubisemiquinone]] [[free radical]]. The first two substrates are released, but this ubisemiquinone intermediate remains bound. In the second step, a second molecule of QH<sub>2</sub> 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 QH<sub>2</sub> as it gains two protons from the mitochondrial matrix. This QH<sub>2</sub> is then released from the enzyme.<ref>{{cite journal |author=Hunte C, Palsdottir H, Trumpower BL |title=Protonmotive pathways and mechanisms in the cytochrome bc1 complex |journal=FEBS Lett. |volume=545 |issue=1 |pages=39–46 |year=2003 |pmid=12788490 |doi=10.1016/S0014-5793(03)00391-0}}</ref>
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| As coenzyme Q is reduced to ubiquinol on the inner side of the membrane and oxidized to ubiquinone on the other, a net transfer of protons across the membrane occurs, adding to the proton gradient.<ref name=Schultz/> 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 QH<sub>2</sub> were used to directly reduce two molecules of cytochrome c, the efficiency would be halved, with only one proton transferred per cytochrome c reduced.<ref name=Schultz/>
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| ===Cytochrome c oxidase (complex IV)===
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| {{details|cytochrome c oxidase}}
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| [[File:Complex IV.svg|thumb|right|Complex IV: [[cytochrome c oxidase]].]]
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| [[Cytochrome c oxidase]], also known as ''complex IV'', is the final protein complex in the electron transport chain.<ref>{{cite journal |author=Calhoun M, Thomas J, Gennis R |title=The cytochrome oxidase superfamily of redox-driven proton pumps |journal=Trends Biochem Sci |volume=19 |issue=8 |pages=325–30 |year=1994 |pmid=7940677 |doi=10.1016/0968-0004(94)90071-X}}</ref> The mammalian enzyme has an extremely complicated structure and contains 13 subunits, two heme groups, as well as multiple metal ion cofactors – in all, three atoms of [[copper]], one of [[magnesium]] and one of [[zinc]].<ref>{{cite journal |author=Tsukihara T, Aoyama H, Yamashita E, Tomizaki T, Yamaguchi H, Shinzawa-Itoh K, Nakashima R, Yaono R, Yoshikawa S. |title=The whole structure of the 13-subunit oxidized cytochrome c oxidase at 2.8 A |journal=Science |volume=272 |issue=5265 |pages=1136–44 |year=1996 |pmid=8638158 |doi=10.1126/science.272.5265.1136 |bibcode=1996Sci...272.1136T}}</ref>
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| This enzyme mediates the final reaction in the electron transport chain and transfers electrons to oxygen, while pumping protons across the membrane.<ref>{{cite journal |author=Yoshikawa S, Muramoto K, Shinzawa-Itoh K, ''et al.'' |title=Proton pumping mechanism of bovine heart cytochrome c oxidase |journal=Biochim. Biophys. Acta |volume=1757 |issue=9–10 |pages=1110–6 |year=2006 |pmid=16904626 |doi=10.1016/j.bbabio.2006.06.004}}</ref> 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:
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| <math>\rm 4\; Cyt\,c_{red} + O_{2} + 8\; H^+_{matrix} \rightarrow 4\; Cyt\,c_{ox} + 2\; H_2O + 4\; H^+_{intermembrane} \! </math>
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| ===Alternative reductases and oxidases===
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| Many eukaryotic organisms have electron transport chains that differ from the much-studied mammalian enzymes described above. For example, [[plant]]s have alternative NADH oxidases, which oxidize NADH in the cytosol rather than in the mitochondrial matrix, and pass these electrons to the ubiquinone pool.<ref>{{cite journal |author=Rasmusson AG, Soole KL, Elthon TE |title=Alternative NAD(P)H dehydrogenases of plant mitochondria |journal=Annual review of plant biology |volume=55 |pages=23–39 |year=2004 |pmid=15725055 |doi=10.1146/annurev.arplant.55.031903.141720}}</ref> These enzymes do not transport protons, and, therefore, reduce ubiquinone without altering the electrochemical gradient across the inner membrane.<ref>{{cite journal |author=Menz RI, Day DA |title=Purification and characterization of a 43-kDa rotenone-insensitive NADH dehydrogenase from plant mitochondria |journal=J. Biol. Chem. |volume=271 |issue=38 |pages=23117–20 |year=1996 |pmid=8798503 |url=http://www.jbc.org/cgi/content/full/271/38/23117 |doi=10.1074/jbc.271.38.23117}}</ref>
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| Another example of a divergent electron transport chain is the ''[[alternative oxidase]]'', which is found in [[plant]]s, as well as some [[fungus|fungi]], [[protist]]s, and possibly some animals.<ref>{{cite journal |author=McDonald A, Vanlerberghe G |title=Branched mitochondrial electron transport in the Animalia: presence of alternative oxidase in several animal phyla |journal=IUBMB Life |volume=56 |issue=6 |pages=333–41 |year=2004 |pmid=15370881 |doi=10.1080/1521-6540400000876}}</ref><ref>{{cite journal |author=Sluse FE, Jarmuszkiewicz W |title=Alternative oxidase in the branched mitochondrial respiratory network: an overview on structure, function, regulation, and role |journal=Braz. J. Med. Biol. Res. |volume=31 |issue=6 |pages=733–47 |year=1998 |pmid=9698817 |doi=10.1590/S0100-879X1998000600003}}</ref> This enzyme transfers electrons directly from ubiquinol to oxygen.<ref>{{cite journal |author=Moore AL, Siedow JN |title=The regulation and nature of the cyanide-resistant alternative oxidase of plant mitochondria |journal=Biochim. Biophys. Acta |volume=1059 |issue=2 |pages=121–40 |year=1991 |pmid=1883834 |doi=10.1016/S0005-2728(05)80197-5}}</ref>
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| The electron transport pathways produced by these alternative NADH and ubiquinone oxidases have lower [[adenosine triphosphate|ATP]] yields than the full pathway. The advantages produced by a shortened pathway are not entirely clear. However, the alternative oxidase is produced in response to stresses such as cold, [[reactive oxygen species]], and infection by pathogens, as well as other factors that inhibit the full electron transport chain.<ref>{{cite journal |author=Vanlerberghe GC, McIntosh L |title=Alternative oxidase: From Gene to Function |journal= Annual Review of Plant Physiology and Plant Molecular Biology|volume=48 |pages=703–34 |year=1997 |pmid=15012279 |doi=10.1146/annurev.arplant.48.1.703}}</ref><ref>{{cite journal |author=Ito Y, Saisho D, Nakazono M, Tsutsumi N, Hirai A |title=Transcript levels of tandem-arranged alternative oxidase genes in rice are increased by low temperature |journal=Gene |volume=203 |issue=2 |pages=121–9 |year=1997 |pmid=9426242 |doi=10.1016/S0378-1119(97)00502-7}}</ref> Alternative pathways might, therefore, enhance an organisms' resistance to injury, by reducing [[oxidative stress]].<ref>{{cite journal |author=Maxwell DP, Wang Y, McIntosh L |title=The alternative oxidase lowers mitochondrial reactive oxygen production in plant cells |url=http://www.pnas.org/cgi/content/full/96/14/8271 |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue=14 |pages=8271–6 |year=1999 |pmid=10393984 |doi=10.1073/pnas.96.14.8271 |pmc=22224|bibcode = 1999PNAS...96.8271M }}</ref>
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| ===Organization of complexes===
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| The original model for how the respiratory chain complexes are organized was that they diffuse freely and independently in the mitochondrial membrane.<ref name=Lenaz>{{cite journal |author=Lenaz G |title=A critical appraisal of the mitochondrial coenzyme Q pool |journal=FEBS Lett. |volume=509 |issue=2 |pages=151–5 |year=2001 |pmid=11741580 |doi=10.1016/S0014-5793(01)03172-6}}</ref> However, recent data suggest that the complexes might form higher-order structures called supercomplexes or "[[respirasome|respirasomes]]."<ref>{{cite journal |author=Heinemeyer J, Braun HP, Boekema EJ, Kouril R |title=A structural model of the cytochrome C reductase/oxidase supercomplex from yeast mitochondria |journal=J. Biol. Chem. |volume=282 |issue=16 |pages=12240–8 |year=2007 |pmid=17322303 |doi=10.1074/jbc.M610545200}}</ref> In this model, the various complexes exist as organized sets of interacting enzymes.<ref>{{cite journal |author=Schägger H, Pfeiffer K |title=Supercomplexes in the respiratory chains of yeast and mammalian mitochondria |journal=EMBO J. |volume=19 |issue=8 |pages=1777–83 |year=2000 |pmid=10775262 |pmc=302020 |doi=10.1093/emboj/19.8.1777}}</ref> These associations might allow channeling of substrates between the various enzyme complexes, increasing the rate and efficiency of electron transfer.<ref>{{cite journal |author=Schägger H |title=Respiratory chain supercomplexes of mitochondria and bacteria |journal=Biochim. Biophys. Acta |volume=1555 |issue=1–3 |pages=154–9 |year=2002 |pmid=12206908 |doi=10.1016/S0005-2728(02)00271-2}}</ref> Within such mammalian supercomplexes, some components would be present in higher amounts than others, with some data suggesting a ratio between complexes I/II/III/IV and the ATP synthase of approximately 1:1:3:7:4.<ref>{{cite journal |author=Schägger H, Pfeiffer K |title=The ratio of oxidative phosphorylation complexes I-V in bovine heart mitochondria and the composition of respiratory chain supercomplexes |journal=J. Biol. Chem. |volume=276 |issue=41 |pages=37861–7 |year=2001 |pmid=11483615 |url=http://www.jbc.org/cgi/content/full/276/41/37861 |doi=10.1074/jbc.M106474200}}</ref> However, the debate over this supercomplex hypothesis is not completely resolved, as some data do not appear to fit with this model.<ref name=Lenaz/><ref>{{cite journal |author=Gupte S, Wu ES, Hoechli L, ''et al.'' |title=Relationship between lateral diffusion, collision frequency, and electron transfer of mitochondrial inner membrane oxidation-reduction components |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=81 |issue=9 |pages=2606–10 |year=1984 |pmid=6326133 |pmc=345118 |doi=10.1073/pnas.81.9.2606|bibcode = 1984PNAS...81.2606G }}</ref>
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| ==Prokaryotic electron transport chains==
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| {{further2|[[Microbial metabolism]]}}
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| 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.<ref>{{cite journal |author=Nealson KH |title=Post-Viking microbiology: new approaches, new data, new insights |journal=Origins of life and evolution of the biosphere: the journal of the International Society for the Study of the Origin of Life |volume=29 |issue=1 |pages=73–93 |year=1999 |pmid=11536899 |doi=10.1023/A:1006515817767}}</ref> 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.<ref>{{cite journal |author=Schäfer G, Engelhard M, Müller V |title=Bioenergetics of the Archaea |journal=Microbiol. Mol. Biol. Rev. |volume=63 |issue=3 |pages=570–620 |year=1999 |pmid=10477309 |pmc=103747}}</ref>
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| 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.<ref name=Ingledew>{{cite journal |author=Ingledew WJ, Poole RK |title=The respiratory chains of Escherichia coli |journal=Microbiol. Rev. |volume=48 |issue=3 |pages=222–71 |year=1984 |pmid=6387427 |pmc=373010}}</ref> 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 [[Standard electrode potential#Non-standard condition|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.
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| {| class="wikitable" style="margin-left: auto; margin-right: auto;"
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| |+ Respiratory enzymes and substrates in ''E. coli''.<ref name=Unden>{{cite journal |author=Unden G, Bongaerts J |title=Alternative respiratory pathways of Escherichia coli: energetics and transcriptional regulation in response to electron acceptors |journal=Biochim. Biophys. Acta |volume=1320 |issue=3 |pages=217–34 |year=1997 |pmid=9230919 |doi=10.1016/S0005-2728(97)00034-0}}</ref>
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| |-
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| !Respiratory enzyme
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| ![[redox|Redox pair]]
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| ! [[Standard electrode potential#Non-standard condition|Midpoint potential]]
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| (Volts)
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| |-
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| | [[Formate dehydrogenase]]
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| | [[Bicarbonate]] / [[Formate]]
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| | <center>−0.43
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| |-
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| | [[Hydrogenase]]
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| | [[Proton]] / [[Hydrogen]]
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| | <center>−0.42
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| |-
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| | [[NADH dehydrogenase]]
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| | [[Nicotinamide adenine dinucleotide|NAD<sup>+</sup>]] / [[Nicotinamide adenine dinucleotide|NADH]]
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| | <center>−0.32
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| |-
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| | [[Glycerol-3-phosphate dehydrogenase]]
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| | [[dihydroxyacetone phosphate|DHAP]] / [[Glycerol 3-phosphate|Gly-3-P]]
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| | <center>−0.19
| |
| |-
| |
| | [[Pyruvate dehydrogenase#Other forms|Pyruvate oxidase]]
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| | [[acetic acid|Acetate]] + [[Carbon dioxide]] / [[pyruvic acid|Pyruvate]]
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| | <center>?
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| |-
| |
| | [[Lactate dehydrogenase]]
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| | [[pyruvic acid|Pyruvate]] / [[Lactic acid|Lactate]]
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| | <center>−0.19
| |
| |-
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| | [[D-amino acid dehydrogenase|<small>D</small>-amino acid dehydrogenase]]
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| | [[Oxoacid|2-oxoacid]] + [[ammonia]] / [[Amino acid|<small>D</small>-amino acid]]
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| | <center>?
| |
| |-
| |
| | [[Quinoprotein glucose dehydrogenase|Glucose dehydrogenase]]
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| | [[gluconic acid|Gluconate]] / [[Glucose]]
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| | <center>−0.14
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| |-
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| | [[Succinate - coenzyme Q reductase|Succinate dehydrogenase]]
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| | [[Fumaric acid|Fumarate]] / [[Succinic acid|Succinate]]
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| | <center>+0.03
| |
| |-
| |
| | [[Ubiquinol oxidase]]
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| | [[Oxygen]] / [[Water]]
| |
| | <center>+0.82
| |
| |-
| |
| | [[Nitrate reductase]]
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| | [[Nitrate]] / [[Nitrite]]
| |
| | <center>+0.42
| |
| |-
| |
| | [[Nitrite reductase]]
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| | [[Nitrite]] / [[Ammonia]]
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| | <center>+0.36
| |
| |-
| |
| | [[DMSO reductase|Dimethyl sulfoxide reductase]]
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| | [[dimethyl sulfoxide|DMSO]] / [[Dimethyl sulfide|DMS]]
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| | <center>+0.16
| |
| |-
| |
| | [[Trimethylamine N-oxide reductase|Trimethylamine ''N''-oxide reductase]]
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| | [[Trimethylamine N-oxide|TMAO]] / [[Trimethylamine|TMA]]
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| | <center>+0.13
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| |-
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| | [[Fumarate reductase]]
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| | [[Fumaric acid|Fumarate]] / [[Succinic acid|Succinate]]
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| | <center>+0.03
| |
| |}
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| 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.<ref name=Ingledew/> 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 [[Succinate - coenzyme Q reductase|succinate dehydrogenase]] and [[fumarate reductase]], respectively.<ref>{{cite journal |author=Cecchini G, Schröder I, Gunsalus RP, Maklashina E |title=Succinate dehydrogenase and fumarate reductase from Escherichia coli |journal=Biochim. Biophys. Acta |volume=1553 |issue=1–2 |pages=140–57 |year=2002 |pmid=11803023 |doi=10.1016/S0005-2728(01)00238-9}}</ref>
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| Some prokaryotes use redox pairs that have only a small difference in midpoint potential. For example, [[nitrification|nitrifying]] bacteria such as ''[[Nitrobacter]]'' oxidize nitrite to nitrate, donating the electrons to oxygen. The small amount of energy released in this reaction is enough to pump protons and generate ATP, but not enough to produce NADH or NADPH directly for use in [[anabolism]].<ref>{{cite journal |author=Freitag A, Bock E|year=1990 |title=Energy conservation in Nitrobacter |journal=FEMS Microbiology Letters |volume=66 |issue=1–3 |pages=157–62 |doi=10.1111/j.1574-6968.1990.tb03989.x}}</ref> 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.<ref>{{cite journal |author=Starkenburg SR, Chain PS, Sayavedra-Soto LA, ''et al.'' |title=Genome Sequence of the Chemolithoautotrophic Nitrite-Oxidizing Bacterium Nitrobacter winogradskyi Nb-255 |journal=Appl. Environ. Microbiol. |volume=72 |issue=3 |pages=2050–63 |year=2006 |pmid=16517654 |url=http://aem.asm.org/cgi/content/full/72/3/2050?view=long&pmid=16517654 |doi=10.1128/AEM.72.3.2050-2063.2006 |pmc=1393235}}</ref><ref>{{cite journal |author=Yamanaka T, Fukumori Y |title=The nitrite oxidizing system of Nitrobacter winogradskyi |journal=FEMS Microbiol. Rev. |volume=4 |issue=4 |pages=259–70 |year=1988 |pmid=2856189}}</ref>
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| Prokaryotes control their use of these electron donors and acceptors by varying which enzymes are produced, in response to environmental conditions.<ref>{{cite journal |author=Iuchi S, Lin EC |title=Adaptation of Escherichia coli to redox environments by gene expression |journal=Mol. Microbiol. |volume=9 |issue=1 |pages=9–15 |year=1993 |pmid=8412675 |doi=10.1111/j.1365-2958.1993.tb01664.x}}</ref> 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.<ref name=Unden/> These respiratory chains therefore have a [[modular design]], with easily interchangeable sets of enzyme systems.
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| In addition to this metabolic diversity, prokaryotes also possess a range of [[isozyme]]s – 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 transfers only one proton per electron, but has a high affinity for oxygen.<ref>{{cite journal |author=Calhoun MW, Oden KL, Gennis RB, de Mattos MJ, Neijssel OM |title=Energetic efficiency of Escherichia coli: effects of mutations in components of the aerobic respiratory chain |journal=J. Bacteriol. |volume=175 |issue=10 |pages=3020–5 |year=1993 |pmid=8491720 |url=http://jb.asm.org/cgi/reprint/175/10/3020.pdf|format=PDF |pmc=204621}}</ref>
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| ==ATP synthase (complex V)==
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| {{further2|[[ATP synthase]]}}
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| 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 and eukaryotes.<ref name=Boyer>{{cite journal |author=Boyer PD |title=The ATP synthase—a splendid molecular machine |journal=Annu. Rev. Biochem. |volume=66 |pages=717–49 |year=1997 |pmid=9242922 |doi=10.1146/annurev.biochem.66.1.717}}</ref> The enzyme uses the energy stored in a proton gradient across a membrane to drive the synthesis of ATP from ADP and [[phosphate]] (P<sub>i</sub>). Estimates of the number of protons required to synthesize one ATP have ranged from three to four,<ref>{{cite journal |author=Van Walraven HS, Strotmann H, Schwarz O, Rumberg B |title=The H+/ATP coupling ratio of the ATP synthase from thiol-modulated chloroplasts and two cyanobacterial strains is four |journal=FEBS Lett. |volume=379 |issue=3 |pages=309–13 |year=1996 |pmid=8603713 |doi=10.1016/0014-5793(95)01536-1}}</ref><ref>{{cite journal |author=Yoshida M, Muneyuki E, Hisabori T |title=ATP synthase—a marvellous rotary engine of the cell |journal=Nature Reviews Molecular Cell Biology |volume=2 |issue=9 |pages=669–77 |year=2001 |pmid=11533724 |doi=10.1038/35089509}}</ref> with some suggesting cells can vary this ratio, to suit different conditions.<ref>{{cite journal |author=Schemidt RA, Qu J, Williams JR, Brusilow WS |title=Effects of Carbon Source on Expression of Fo Genes and on the Stoichiometry of the c Subunit in the F1Fo ATPase of Escherichia coli |journal=J. Bacteriol. |volume=180 |issue=12 |pages=3205–8 |year=1998 |pmid=9620972 |pmc=107823}}</ref>
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| :<math>\rm ADP + P_i + 4\; H^+_{intermembrane} \rightleftharpoons ATP + H_2O + 4\; H^+_{matrix} \! </math>
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| This [[phosphorylation]] reaction is an [[chemical equilibrium|equilibrium]], which can be shifted by altering the proton-motive force. In the absence of a proton-motive force, the ATP synthase reaction will run from right to left, hydrolyzing ATP and pumping protons out of the matrix across the membrane. However, when the proton-motive force is high, the reaction is forced to run in the opposite direction; it proceeds from left to right, allowing protons to flow down their concentration gradient and turning ADP into ATP.<ref name=Boyer/> Indeed, in the closely related [[V-ATPase|vacuolar type H+-ATPases]], the hydrolysis reaction is used to acidify cellular compartments, by pumping protons and hydrolysing ATP.<ref>{{cite journal |author=Nelson N, Perzov N, Cohen A, Hagai K, Padler V, Nelson H |title=The cellular biology of proton-motive force generation by V-ATPases |journal=J. Exp. Biol. |volume=203 |issue=Pt 1 |pages=89–95 |date=1 January 2000|pmid=10600677 |url=http://jeb.biologists.org/cgi/reprint/203/1/89}}</ref>
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| 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 [[kilodalton]]s.<ref>{{cite journal |author=Rubinstein JL, Walker JE, Henderson R |title=Structure of the mitochondrial ATP synthase by electron cryomicroscopy |journal=EMBO J. |volume=22 |issue=23 |pages=6182–92 |year=2003 |pmid=14633978 |pmc=291849 |doi=10.1093/emboj/cdg608}}</ref> The portion embedded within the membrane is called F<sub>O</sub> and contains a ring of c subunits and the proton channel. The stalk and the ball-shaped headpiece is called F<sub>1</sub> and is the site of ATP synthesis. The ball-shaped complex at the end of the F<sub>1</sub> 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.<ref>{{cite journal |author=Leslie AG, Walker JE |title=Structural model of F1-ATPase and the implications for rotary catalysis |journal=Philosophical Transactions of the Royal Society B |volume=355 |issue=1396 |pages=465–71 |year=2000 |pmid=10836500 |pmc=1692760 |doi=10.1098/rstb.2000.0588}}</ref> Both the α and β subunits bind nucleotides, but only the β subunits catalyze the ATP synthesis reaction. Reaching along the side of the F<sub>1</sub> 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.
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| As protons cross the membrane through the channel in the base of ATP synthase, the F<sub>O</sub> proton-driven motor rotates.<ref>{{cite journal |author=Noji H, Yoshida M |title=The rotary machine in the cell, ATP synthase |journal=J. Biol. Chem. |volume=276 |issue=3 |pages=1665–8 |year=2001 |pmid=11080505 |url=http://www.jbc.org/cgi/content/full/276/3/1665 |doi=10.1074/jbc.R000021200}}</ref> 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.<ref>{{cite journal |author=Capaldi R, Aggeler R |title=Mechanism of the F(1)F(0)-type ATP synthase, a biological rotary motor |journal=Trends Biochem Sci |volume=27 |issue=3 |pages=154–60 |year=2002 |pmid=11893513 |doi=10.1016/S0968-0004(01)02051-5}}<!--PubMed listing does use incorrect "F0" notation--></ref> 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.<ref name=Dimroth>{{cite journal |author=Dimroth P, von Ballmoos C, Meier T |title=Catalytic and mechanical cycles in F-ATP synthases: Fourth in the Cycles Review Series |pmc=1456893 |journal=EMBO Reports|volume=7 |issue=3 |pages=276–82 |year=2006 |pmid=16607397 |doi=10.1038/sj.embor.7400646}}</ref>
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| [[File:ATPsyn.gif|thumb|220px|right|Mechanism of [[ATP synthase]]. ATP is shown in red, ADP and phosphate in pink and the rotating γ subunit in black.]]
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| This ATP synthesis reaction is called the ''binding change mechanism'' and involves the active site of a β subunit cycling between three states.<ref name=Gresser>{{cite journal |author=Gresser MJ, Myers JA, Boyer PD |title=Catalytic site cooperativity of beef heart mitochondrial F1 adenosine triphosphatase. Correlations of initial velocity, bound intermediate, and oxygen exchange measurements with an alternating three-site model |journal=J. Biol. Chem. |volume=257 |issue=20 |pages=12030–8 |date=25 October 1982|pmid=6214554 |url=http://www.jbc.org/cgi/reprint/257/20/12030}}</ref> 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 [[Dissociation constant|affinity]]. Finally, the active site cycles back to the open state, releasing ATP and binding more ADP and phosphate, ready for the next cycle.
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| 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.<ref>{{cite journal |author=Dimroth P |title=Bacterial sodium ion-coupled energetics |journal=Antonie Van Leeuwenhoek |volume=65 |issue=4 |pages=381–95 |year=1994 |pmid=7832594 |doi=10.1007/BF00872221}}</ref><ref name=Becher>{{cite journal |author=Becher B, Müller V |title=Delta mu Na+ drives the synthesis of ATP via an delta mu Na(+)-translocating F1FO-ATP synthase in membrane vesicles of the archaeon Methanosarcina mazei Gö1 |journal=J. Bacteriol. |volume=176 |issue=9 |pages=2543–50 |year=1994 |pmid=8169202 |pmc=205391}}</ref> Archaea such as ''[[Methanococcus]]'' also contain the A<sub>1</sub>A<sub>o</sub> 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 A<sub>1</sub>A<sub>o</sub> form of the enzyme is a specialized sodium-driven ATP synthase,<ref>{{cite journal |author=Müller V |title=An exceptional variability in the motor of archaeal A1A0 ATPases: from multimeric to monomeric rotors comprising 6–13 ion binding sites |journal=J. Bioenerg. Biomembr. |volume=36 |issue=1 |pages=115–25 |year=2004 |pmid=15168615 |doi=10.1023/B:JOBB.0000019603.68282.04}}</ref> but this might not be true in all cases.<ref name=Becher/>
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| ==Reactive oxygen species==
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| {{Further2|[[Oxidative stress]] and [[Antioxidant]]}}
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| Molecular oxygen is an ideal terminal [[electron acceptor]] because it is a strong oxidizing agent. The reduction of oxygen does involve potentially harmful intermediates.<ref name=Davies>{{cite journal |author=Davies K |title=Oxidative stress: the paradox of aerobic life |journal=Biochem Soc Symp |volume=61 |pages=1–31 |year=1995 |pmid=8660387}}</ref> Although the transfer of four electrons and four protons reduces oxygen to water, which is harmless, transfer of one or two electrons produces [[superoxide]] or [[peroxide]] anions, which are dangerously reactive.
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| :<math> \begin{matrix} \quad & {\mathrm{e}^-} & \quad & {\mathrm{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}</math>
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| These [[reactive oxygen species]] and their reaction products, such as the [[hydroxyl]] radical, are very harmful to cells, as they oxidize proteins and cause [[mutation]]s in [[DNA]]. This cellular damage might contribute to [[disease]] and is proposed as one cause of [[free-radical theory of aging|aging]].<ref>{{cite journal |author=Rattan SI |title=Theories of biological aging: genes, proteins, and free radicals |journal=Free Radic. Res. |volume=40 |issue=12 |pages=1230–8 |year=2006 |pmid=17090411 |doi=10.1080/10715760600911303}}</ref><ref>{{cite journal |author=Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J |title=Free radicals and antioxidants in normal physiological functions and human disease |journal=Int. J. Biochem. Cell Biol. |volume=39 |issue=1 |pages=44–84 |year=2007 |pmid=16978905 |doi=10.1016/j.biocel.2006.07.001}}</ref>
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| 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.<ref name=Raha>{{cite journal |author=Raha S, Robinson B |title=Mitochondria, oxygen free radicals, disease and ageing |journal=Trends Biochem Sci |volume=25 |issue=10 |pages=502–8 |year=2000 |pmid=11050436 |doi=10.1016/S0968-0004(00)01674-1}}</ref> 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.<ref>{{cite journal|author=Finkel T, Holbrook NJ|title=Oxidants, oxidative stress and the biology of ageing|journal=Nature|year=2000|pages=239–47|volume=408|issue=6809|pmid=11089981|doi=10.1038/35041687}}</ref> As the production of reactive oxygen species by these proton-pumping complexes is greatest at high membrane potentials, it has been proposed that mitochondria regulate their activity to maintain the membrane potential within a narrow range that balances ATP production against oxidant generation.<ref>{{cite journal |author=Kadenbach B, Ramzan R, Wen L, Vogt S |title=New extension of the Mitchell Theory for oxidative phosphorylation in mitochondria of living organisms |journal=Biochim. Biophys. Acta |volume= 1800|pages= 205–212|date=May 2009 |pmid=19409964 |doi=10.1016/j.bbagen.2009.04.019 |issue=3}}</ref> For instance, oxidants can activate [[uncoupling protein]]s that reduce membrane potential.<ref>{{cite journal |author=Echtay KS, Roussel D, St-Pierre J, ''et al.'' |title=Superoxide activates mitochondrial uncoupling proteins |journal=Nature |volume=415 |issue=6867 |pages=96–9 |date=January 2002 |pmid=11780125 |doi=10.1038/415096a|bibcode = 2002Natur.415...96E }}</ref>
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| To counteract these reactive oxygen species, cells contain numerous [[antioxidant]] systems, including antioxidant [[vitamin]]s such as [[vitamin C]] and [[vitamin E]], and antioxidant enzymes such as [[superoxide dismutase]], [[catalase]], and [[peroxidases]],<ref name=Davies/> which detoxify the reactive species, limiting damage to the cell.
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| ==Inhibitors==
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| There are several well-known [[drug]]s and [[toxin]]s that inhibit oxidative phosphorylation. Although any one of these toxins inhibits only one enzyme in the electron transport chain, inhibition of any step in this process will halt the rest of the process. For example, if [[oligomycin]] inhibits ATP synthase, protons cannot pass back into the mitochondrion.<ref name=Joshi/> 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<sup>+</sup> falls below the concentration that these enzymes can use.
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| {| class="wikitable" style="margin-left: auto; margin-right: auto;"
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| !Compounds
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| !Use
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| !Effect on oxidative phosphorylation
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| |-
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| |[[Cyanide]]<br />[[carbon monoxide|Carbon monoxide]]<br />[[Azide]]
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| |align="center" |Poisons
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| |Inhibit the electron transport chain by binding more strongly than oxygen to the [[iron|Fe]]–[[copper|Cu]] center in cytochrome c oxidase, preventing the reduction of oxygen.<ref>{{cite journal |author=Tsubaki M |title=Fourier-transform infrared study of cyanide binding to the Fea3-CuB binuclear site of bovine heart cytochrome c oxidase: implication of the redox-linked conformational change at the binuclear site |journal=Biochemistry |volume=32 |issue=1 |pages=164–73 |year=1993 |pmid=8380331 |doi=10.1021/bi00052a022 |last2=Yoshikawa |first2=Shinya}}</ref>
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| |-
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| |[[Oligomycin]]
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| |align="center" |[[Antibiotic]]
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| ||Inhibits ATP synthase by blocking the flow of protons through the F<sub>o</sub> subunit.<ref name=Joshi>{{cite journal |author=Joshi S, Huang YG |title=ATP synthase complex from bovine heart mitochondria: the oligomycin sensitivity conferring protein is essential for dicyclohexyl carbodiimide-sensitive ATPase |journal=Biochim. Biophys. Acta |volume=1067 |issue=2 |pages=255–8 |year=1991 |pmid=1831660 |doi=10.1016/0005-2736(91)90051-9}}</ref>
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| |-
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| |[[Carbonyl cyanide m-chlorophenyl hydrazone|CCCP]]<br />[[2,4-Dinitrophenol]]
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| |align="center" |Poisons
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| ||[[Ionophore]]s that disrupt the proton gradient by carrying protons across a membrane. This ionophore [[uncouples]] proton pumping from ATP synthesis because it carries protons across the inner mitochondrial membrane.<ref>{{cite journal |author=Heytler PG |title=Uncouplers of oxidative phosphorylation |journal=Meth. Enzymol. |volume=55 |pages=462–42 |year=1979 |pmid=156853 |doi=10.1016/0076-6879(79)55060-5 |series=Methods in Enzymology |isbn=978-0-12-181955-2}}</ref>
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| |-
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| |[[Rotenone]]
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| |align="center" |[[Pesticide]]
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| ||Prevents the transfer of electrons from complex I to ubiquinone by blocking the ubiquinone-binding site.<ref>{{cite journal |author=Lambert AJ, Brand MD |title=Inhibitors of the quinone-binding site allow rapid superoxide production from mitochondrial NADH: ubiquinone oxidoreductase (complex I) |journal=J. Biol. Chem. |volume=279 |issue=38 |pages=39414–20 |year=2004 |pmid=15262965 |url=http://www.jbc.org/cgi/content/full/279/38/39414 |doi=10.1074/jbc.M406576200}}</ref>
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| |-
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| |[[Malonate]] and [[oxaloacetate]]
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| |align="center" |
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| ||Competitive inhibitors of succinate dehydrogenase (complex II).<ref>{{cite journal |author=Dervartanian DV, Veeger C. |title=Studies on succinate dehydrogenase. I. Spectral properties of the purified enzyme and formation of enzyme-competitive inhibitor complexes |journal=Biochim. Biophys. Acta |volume=92 |pages=233–47 |date=November 1964 |pmid=14249115}}</ref>
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| |}
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| Not all inhibitors of oxidative phosphorylation are toxins. In [[brown adipose tissue]], regulated proton channels called [[uncoupling protein]]s can uncouple respiration from ATP synthesis.<ref>{{cite journal |author=Ricquier D, Bouillaud F |title=The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP |journal=Biochem. J. |volume=345 |pages=161–79 |year=2000 |pmid=10620491 |pmc=1220743 |doi=10.1042/0264-6021:3450161 |issue=2}}</ref> This rapid respiration produces heat, and is particularly important as a way of maintaining [[body temperature]] for [[hibernation|hibernating]] animals, although these proteins may also have a more general function in cells' responses to stress.<ref>{{cite journal |author=Borecký J, Vercesi AE |title=Plant uncoupling mitochondrial protein and alternative oxidase: energy metabolism and stress |journal=Biosci. Rep. |volume=25 |issue=3–4 |pages=271–86 |year=2005 |pmid=16283557 |doi=10.1007/s10540-005-2889-2}}</ref>
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| ==History==
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| {{further2|[[History of biochemistry]] and [[History of molecular biology]]}}
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| The field of oxidative phosphorylation began with the report in 1906 by [[Arthur Harden]] of a vital role for phosphate in cellular [[fermentation (biochemistry)|fermentation]], but initially only [[sugar phosphates]] were known to be involved.<ref>{{cite journal |author=Harden A, Young WJ. |title=The alcoholic ferment of yeast-juice |journal=Proceedings of the Royal Society |volume=B |issue=77 |pages=405–20 |year=1906 |doi=10.1098/rspb.1906.0029}}</ref> However, in the early 1940s, the link between the oxidation of sugars and the generation of ATP was firmly established by [[Herman Kalckar]],<ref>{{cite journal |author=Kalckar HM |title=Origins of the concept oxidative phosphorylation |journal=Mol. Cell. Biochem. |volume=5 |issue=1–2 |pages=55–63 |year=1974 |pmid=4279328 |doi=10.1007/BF01874172}}</ref> confirming the central role of ATP in energy transfer that had been proposed by [[Fritz Albert Lipmann]] in 1941.<ref>{{cite journal |author=Lipmann F, |title=Metabolic generation and utilization of phosphate bond energy |journal=Adv Enzymol |volume=1 |pages=99–162 |year=1941}}</ref> 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.<ref>{{cite journal |author=Friedkin M, Lehninger AL. |title=Esterification of inorganic phosphate coupled to electron transport between dihydrodiphosphopyridine nucleotide and oxygen |journal=J. Biol. Chem. |volume=178 |issue=2 |pages=611–23 |date=1 April 1949|url=http://www.jbc.org/cgi/reprint/178/2/611 |pmid=18116985}}</ref>
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| 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.<ref>{{cite journal |author=Slater EC. |title=Mechanism of Phosphorylation in the Respiratory Chain |journal=Nature |volume=172 |issue=4387 |pages=975–8 |year=1953 |doi=10.1038/172975a0 |pmid=13111237|bibcode = 1953Natur.172..975S }}</ref> This puzzle was solved by [[Peter D. Mitchell]] with the publication of the [[chemiosmotic theory]] in 1961.<ref>{{cite journal |author=Mitchell P. |title=Coupling of Phosphorylation to Electron and Hydrogen Transfer by a Chemi-Osmotic type of Mechanism |journal=Nature |volume=191 |issue=4784 |pages=144–8 |year=1961 |pmid=13771349 |doi=10.1038/191144a0 |bibcode=1961Natur.191..144M}}</ref> At first, this proposal was highly controversial, but it was slowly accepted and Mitchell was awarded a [[Nobel Prize|Nobel prize]] in 1978.<ref>{{cite web |url=http://www-biology.ucsd.edu/~msaier/transport/petermitchell/MitchellFrame-1.html |title=Peter Mitchell and the Vital Force |author=Milton H. Saier Jr |accessdate=2007-08-23}}</ref><ref>{{cite web |url=http://nobelprize.org/nobel_prizes/chemistry/laureates/1978/mitchell-lecture.pdf |title=David Keilin's Respiratory Chain Concept and Its Chemiosmotic Consequences |accessdate=2007-07-21 |last=Mitchell |first=Peter |year=1978 |format=Pdf |work=Nobel lecture |publisher=Nobel Foundation}}</ref> Subsequent research concentrated on purifying and characterizing the enzymes involved, with major contributions being made by [[David E. Green]] on the complexes of the electron-transport chain, as well as [[Efraim Racker]] on the ATP synthase.<ref>{{cite journal |author=Pullman ME, Penefsky HS, Datta A, and Racker E. |title=Partial Resolution of the Enzymes Catalyzing Oxidative Phosphorylation. I. Purification and Properties of Soluble, Dinitrophenol-stimulated Adenosine Triphosphatase |journal=J. Biol. Chem. |volume=235 |issue=11 |pages=3322–9 |date=1 November 1960|url=http://www.jbc.org/cgi/reprint/235/11/3322 |pmid=13738472}}</ref> A critical step towards solving the mechanism of the ATP synthase was provided by [[Paul D. Boyer]], by his development in 1973 of the "binding change" mechanism, followed by his radical proposal of rotational catalysis in 1982.<ref name=Gresser/><ref>{{cite journal |author=Boyer PD, Cross RL, Momsen W |title=A New Concept for Energy Coupling in Oxidative Phosphorylation Based on a Molecular Explanation of the Oxygen Exchange Reactions |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=70 |issue=10 |pages=2837–9 |year=1973 |pmid=4517936 |pmc=427120 |doi=10.1073/pnas.70.10.2837|bibcode = 1973PNAS...70.2837B }}</ref> More recent work has included [[x-ray crystallography|structural studies]] on the enzymes involved in oxidative phosphorylation by [[John E. Walker]], with Walker and Boyer being awarded a Nobel Prize in 1997.<ref>{{cite web |url=http://nobelprize.org/nobel_prizes/chemistry/laureates/1997/ |title=The Nobel Prize in Chemistry 1997 |accessdate=2007-07-21 |publisher=Nobel Foundation}}</ref>
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| ==See also==
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| *[[Respirometry]]
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| *[[TIM/TOM Complex]]
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| ==References==
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| {{Reflist|2}}
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| ==Further reading==
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| '''Introductory'''
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| *{{cite book|author=Nelson DL|coauthors=Cox MM|title=Lehninger Principles of Biochemistry|edition=4th|publisher=W. H. Freeman|year=2004|isbn=0-7167-4339-6}}
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| *{{cite book|author=Schneider ED|coauthors=Sagan D|title=Into the Cool: Energy Flow, Thermodynamics and Life|edition=1st|publisher=University of Chicago Press|year=2006|isbn=0-226-73937-6}}
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| *{{cite book|author=[[Nick Lane|Lane N]] |title=Power, Sex, Suicide: Mitochondria and the Meaning of Life |edition=1st|publisher=Oxford University Press, USA |year=2006|isbn=0-19-920564-7}}
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| '''Advanced'''
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| *{{cite book|author=Nicholls DG|coauthors=Ferguson SJ|title=Bioenergetics 3 |edition=1st|publisher=Academic Press|year=2002|isbn=0-12-518121-3}}
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| *{{cite book|author=Haynie D|title=Biological Thermodynamics |edition=1st|publisher=Cambridge University Press|year=2001|isbn=0-521-79549-4}}
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| *{{cite book|author=Rajan SS|title=Introduction to Bioenergetics |edition=1st|publisher=Anmol |year=2003|isbn=81-261-1364-2}}
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| *{{cite book|author=Wikstrom M (Ed)|title=Biophysical and Structural Aspects of Bioenergetics |edition=1st|publisher=Royal Society of Chemistry |year=2005|isbn=0-85404-346-2}}
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| ==External links==
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| '''General resources'''
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| *[http://www.wiley.com/legacy/college/boyer/0470003790/animations/electron_transport/electron_transport.htm Animated diagrams illustrating oxidative phosphorylation] [[John Wiley & Sons|Wiley and Co]] ''Concepts in Biochemistry''
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| *[http://www.life.uiuc.edu/crofts/bioph354/ On-line biophysics lectures] Antony Crofts, [[University of Illinois at Urbana-Champaign]]
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| *[http://www.youtube.com/watch?v=PjdPTY1wHdQ ATP Synthase] Graham Johnson
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| '''Structural resources'''
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| *[[Protein Data Bank|PDB]] molecule of the month:
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| **[http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb72_1.html ATP synthase]
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| **[http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb36_1.html Cytochrome c]
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| **[http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb5_1.html Cytochrome c oxidase]
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| *Interactive molecular models at [[Universidade Fernando Pessoa]]:
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| **[http://www2.ufp.pt/~pedros/anim/2frame-ien.htm NADH dehydrogenase]
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| **[http://www2.ufp.pt/~pedros/anim/2frame-iien.htm succinate dehydrogenase]
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| **[http://www2.ufp.pt/~pedros/anim/2frame-iiien.htm Coenzyme Q - cytochrome c reductase]
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| **[http://www2.ufp.pt/~pedros/anim/2frame-iven.htm cytochrome c oxidase]
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| {{Electron transport chain}}
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| {{Cellular respiration}}
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| {{featured article}}
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| {{DEFAULTSORT:Oxidative Phosphorylation}}
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| [[Category:Cellular respiration]]
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| [[Category:Integral membrane proteins]]
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| [[Category:Metabolism]]
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| {{Link FA|pt}}
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