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
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.
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 O2 by NADH to pump
protons 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.
NADH-coenzyme Q oxidoreductase (complex I) . The abbreviations are discussed in the text.
NADH-coenzyme Q oxidoreductase, also known as
NADH dehydrogenase or
complex I, is the first protein in the electron transport chain. Complex I is a giant
enzyme with the mammalian complex I having 46 subunits and a molecular mass of about . The structure is known in detail only from a bacterium; in most organisms the complex resembles a boot with a large "ball" poking out from the membrane into the mitochondrion. 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 that is catalyzed by this enzyme is the two electron oxidation of
NADH by
coenzyme Q10 or
ubiquinone (represented as Q in the equation below), a lipid-soluble
quinone that is found in the mitochondrion membrane: {{NumBlk|:|NADH + Q + 5H+_{matrix} -> NAD+ + QH2 + 4H+_{intermembrane}|}} 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, FMNH2. The electrons are then transferred through a series of iron–sulfur clusters: the second kind of prosthetic group present in the complex. Finally, the electrons are transferred from the chain of iron–sulfur clusters to a ubiquinone molecule in the membrane. 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
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. It oxidizes
succinate to
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. {{NumBlk|:|{Succinate} + Q -> {Fumarate} + QH2|}} 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. 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.
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. 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. {{NumBlk|:|ETF_{red}{} + Q -> ETF_{ox}{} + QH2|}} In mammals, this metabolic pathway is important in
beta oxidation of
fatty acids and catabolism of
amino acids and
choline, as it accepts electrons from multiple
acetyl-CoA dehydrogenases. In plants, ETF-Q oxidoreductase is also important in the metabolic responses that allow survival in extended periods of darkness.
Q-cytochrome c oxidoreductase (complex III) . After each step, Q (in the upper part of the figure) leaves the enzyme.
Q-cytochrome c oxidoreductase is also known as
cytochrome c reductase,
cytochrome bc1 complex, or simply
complex III. In mammals, this enzyme is a
dimer, with each subunit complex containing 11 protein subunits, an [2Fe-2S] iron–sulfur cluster and three
cytochromes: one
cytochrome c1 and two b
cytochromes. 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. 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. {{NumBlk|:|QH2{} + 2 Cyt\, c_{ox}{} + 2H+_{matrix} -> Q{} + 2 Cyt\, c_{red}{} + 4H+_{intermembrane}|}} 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. 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. 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. 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. This enzyme mediates the final reaction in the electron transport chain and transfers electrons to oxygen and hydrogen (protons), while pumping protons across the membrane. The final
electron acceptor oxygen 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: {{NumBlk|:|4 Cyt\,c_{red}{} + O2{} + 8H+_{matrix} -> 4 Cyt\,c_{ox}{} + 2H2O{} + 4H+_{intermembrane}|}}
Alternative reductases and oxidases Many eukaryotic organisms have electron transport chains that differ from the much-studied mammalian enzymes described above. For example,
plants have alternative NADH oxidases, which oxidize NADH in the cytosol rather than in the mitochondrial matrix, and pass these electrons to the ubiquinone pool. These enzymes do not transport protons, and, therefore, reduce ubiquinone without altering the electrochemical gradient across the inner membrane. 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. This enzyme transfers electrons directly from ubiquinol to oxygen. The electron transport pathways produced by these alternative NADH and ubiquinone oxidases have lower
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. Alternative pathways might, therefore, enhance an organism's resistance to injury, by reducing
oxidative stress.
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. However, recent data suggest that the complexes might form higher-order structures called supercomplexes or "
respirasomes". In this model, the various complexes exist as organized sets of interacting enzymes. These associations might allow channeling of substrates between the various enzyme complexes, increasing the rate and efficiency of electron transfer. 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. However, the debate over this supercomplex hypothesis is not completely resolved, as some data do not appear to fit with this model. == Prokaryotic electron transport chains ==