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Respiratory Electron Transfer Chain

The respiratory electron transport chain , also the electron transport chain (abbr. ETC , English ETC, Electron transport chain ) is a system of transmembrane proteins and electron carriers necessary to maintain energy balance. ETC maintains a balance due to the transfer of electrons and protons from NADH and FADH 2 to the electron acceptor. In the case of aerobic respiration, the acceptor may be molecular oxygen (O 2 ). In the case of anaerobic respiration, the acceptor can be NO 3 - , NO 2 - , Fe 3+ , fumarate , dimethyl sulfoxide , sulfur , SO 4 2− , CO 2 , etc. ETC in prokaryotes is localized in the MTC , in eukaryotes - on the inner membrane mitochondria . [1] Electron carriers are arranged in order of decreasing electron affinity, that is, by their redox potential , where the acceptor has the strongest electron affinity. Therefore, the electron transport throughout the chain proceeds spontaneously with the release of energy. Energy release into the intermembrane space during electron transfer occurs in steps, in the form of a proton (H + ). Protons from the intermembrane space fall into the proton pump , where proton potential is induced. The proton potential is converted by ATP synthase to the energy of the chemical bonds of ATP . The conjugate work of ETC and ATP synthase is called oxidative phosphorylation .

Mitochondrial electron transport chain

The mitochondrial electron transport chain is the site of oxidative phosphorylation in eukaryotes. NADH and succinate formed during the tricarboxylic acid cycle are oxidized, and their energy is transferred to ATP synthase, which synthesizes ATP for it.

In eukaryotic mitochondria, the electron transfer chain begins with the oxidation of NADH and the reduction of ubiquinone Q by complex I. Next, complex II oxidizes succinate to fumarate and restores ubiquinone Q. Ubiquinone Q is oxidized and reduced by cytochrome with complex III. At the end of the chain, complex IV catalyzes the transfer of electrons from cytochrome c to oxygen to form water . As a result of the reaction, for each conditionally released 6 protons and 6 electrons , 2 water molecules are released due to the waste of 1 O 2 molecule and 10 NAD H molecules.

NADH-dehydrogenase complex

Main article: NADH-dehydrogenase complex

Complex I or NADH-dehydrogenase complex oxidizes NAD-H . This complex plays a central role in the processes of cellular respiration and oxidative
phosphorylation . Almost 40% of the proton gradient , for the synthesis of ATP , is created by this complex [2] . Complex I oxidizes NADH and restores one molecule of ubiquinone , which is released into the membrane. For each oxidized molecule, NADH complex transports four protons through the membrane. The NADH-dehydrogenase complex takes two electrons from it and transfers them to the ubiquinone . Ubiquinone is lipid soluble . Ubiquinone inside the membrane diffuses to complex III. At the same time, complex I pumps 2 protons and 2 electrons from the matrix into the mitochondria .

Cofactors

 
Electron-transport chain of complex I. Gray arrows - an unlikely or not existing transport path

All prosthetic groups of the NADH-dehydrogenase complex (one flavin mononucleotide (FAD) and from 8 to 9 iron-gray clusters ) are located in the peripheral water-soluble domain. In mammals, as in all vertebrates , there are eight of them [3] . Seven clusters form an electron-transport chain, ~ 96 Å long, from FMN to the ubiquinone binding site. Based on current data, it is believed that electron transfer occurs in the following way: NADH → FMN → N3 → N1b → N4 → N5 → N6a → N6b → N2 → Q.

First, two electrons are transferred to flavin, and then they are transmitted one by one through a chain of clusters to the quinone binding site and restore it to the state Q − 2 . Cluster N1a is located near the flavin cofactor and at some distance from the main electron transfer chain. This cluster is highly conserved in different species ; believe that it controls the speed of electron transport inside the complex, transferring an electron with FMN [4] . There is a model according to which one of the electrons from the flavin goes along the trunk path to the quinone , and the other is stored in the cluster N1a and later returns to the main chain, through flavosemiquinone. Perhaps such a mechanism allows to reduce the formation of reactive oxygen species on the reduced flavine. In addition, it allows stabilizing (up to a millisecond ) the state when the last cluster N2 is restored, but there is no second electron to complete the restoration of ubiquinone. Such a state may be necessary for conformational changes associated with proton transport.

Part of the clusters in the chain (N3, N4 and N6a) have a high redox potential (redox potential) at a level of –0.25 V , while the other three (N1b, N5 and N6b) have lower potentials. As a result, the redox potential on the electron path changes like a roller coaster . Such a curve of change in the energy state is characteristic of many redox enzymes: it allows you to optimize the rate of electron transport and achieve efficient energy transfer [4] .

Cluster N5 has a very low potential and limits the speed of the total electron flux throughout the chain. Instead of ligands common for iron-sulfur centers (four cysteine ​​residues ), it is coordinated by three cysteine ​​residues and one histidine residue, and is also surrounded by charged polar residues, although it is located deep in the enzyme [4] .

An unusual ligand has a terminal cluster of the chain - N2. Its redox potential is the highest of all the clusters (from –0.1 to –0.15 V). It is associated with four consecutive cysteine ​​residues located in the polypeptide chain, which creates an intense conformation. Because of this, when it is restored, conformational changes occur in neighboring chains, possibly related to proton transport [4] .

Cluster N7 is present only in complex I of some bacteria. It is far removed from the rest of the clusters and cannot exchange electrons with them, so it seems to be a relic . In some bacterial complexes related to complex I, four conserved cysteine ​​residues were found between N7 and the remaining clusters, and complex I of the Aquifex aeolicus bacterium was found to have an additional Fe 4 S 4 cluster connecting N7 with the rest of the clusters. From this it follows that in A. aeolicus complex I, apart from NADH, can use another electron donor, which transfers them via N7 [5] .

Reaction

The NADH-dehydrogenase complex oxidizes NADH formed in the matrix during the tricarboxylic acid cycle . Electrons from NADH are used to restore the membrane carrier, ubiquinone Q, which transports them to the next complex of the mitochondrial electron transport chain, complex III, or the cytochrome – bc 1 complex [21] .

The NADH-dehydrogenase complex functions as a proton pump : for each oxidized NADH and reduced Q, four protons are pumped through the membrane into the intermembrane space [6] :

NADH + H + + Q + 4H + in → NAD + + QH 2 + 4H + out

The electrochemical potential formed during the reaction is used to synthesize ATP . The reaction catalyzed by complex I is reversible, this process is called aerobic succinate- induced reduction of NAD + . Under conditions of a large potential on the membrane and an excess of reduced ubiquinols, the complex can reduce NAD + using their electrons and pass protons back into the matrix. This phenomenon is usually observed when there is a lot of succinate, but little oxaloacetate or malate . Ubiquinone is reduced by enzymes succinate dehydrogenase , or mitochondrial . Under conditions of a high proton gradient, the affinity of the complex for ubiquinol increases, and the redox potential of ubiquinol decreases due to an increase in its concentration, which makes it possible to transport electrons back through the electric potential of the inner mitochondrial membrane to NAD [7] . This phenomenon was observed in the laboratory, but it is not known whether it has a place in the living cell.

Proton Transport Mechanism
 
Scheme of action of complex I

At the initial stages of the study of complex I, a model was widely discussed, based on the assumption that a system similar to the operates in the complex. However, later studies did not detect any internally related quinones in complex I and completely refuted this hypothesis [8] .

 
Bacterial Na + / H + antiport

The NADH-dehydrogenase complex, apparently, has a unique proton transport mechanism through conformational changes of the enzyme itself. The ND2, ND4 and ND5 subunits are called antiport-like since they are homologous to each other and bacterial Mrp Na + / H + antiports. These three subunits form three main proton channels, which consist of conservative charged amino acid residues (mainly lysine and glutamate ). The fourth proton channel is formed by part of the Nqo8 subunit and the small ND6, ND4L and ND3 subunits. The channel is similar in structure to similar channels of anti-port-like subunits, but contains unusually many densely packed glutamate residues from the matrix, for which it received the name E-channel (Latin E is used as the standard designation for glutamate). An elongation extends from the C-terminus of the ND5 subunit, consisting of two transmembrane helices joined by an unusually long (110 Å) α-helix [4] (HL), which, passing along the side of the complex facing the matrix, physically connects all three antiport-like subunits, and possibly involved in the conjugation of electron transport with conformational rearrangement. Another mating element, βH, is formed by a series of overlapping and α-helices, it is located on the opposite, periplasmic side of the complex [9] . It is still completely unknown how exactly the transport of electrons is associated with proton transfer. It is believed that the powerful negative charge of the N2 cluster can push apart the surrounding polypeptides, causing those conformational changes that in some way spread to all antiport-like subunits located rather far from each other. Another hypothesis suggests that a change in conformation causes stabilized u2 quinol Q- 2 with an extremely low redox potential and a negative charge in an unusually long binding site of ubiquinone. Many details of the kinetics of conformational changes and the associated proton transport remain unknown [9] .

Inhibitors

The most studied inhibitor of complex I is rotenone (widely used as an organic pesticide ). Rotenone and rotenoids are isoflavones , which are present in the roots of several genera of tropical plants such as Anthony ( Loganiaceae ), Derris and Lonchocarpus ( Fabaceae ). Rotenone has long been used as an insecticide and fish poison, as mitochondria of insects and fish are especially sensitive to it. It is known that the native inhabitants of French Guiana and other Indians of South America used rotenone-containing plants for fishing as early as the 17th century [10] . Rotenone interacts with the ubiquinone binding site and competes with the main substrate. It was shown that long-term systemic suppression of complex I with rotenone can induce the selective death of dopaminergic neurons (secreting dopamine as a neurotransmitter ) [11] . Piericidin A acts in a similar way, another powerful inhibitor of complex I, structurally similar to ubiquinone. This group also includes sodium amytal , a derivative of barbituric acid [12] .

Despite the more than 50-year study of complex I, it was not possible to detect inhibitors that block the transfer of electrons within the complex. Hydrophobic inhibitors, such as rotenone or piericidin, simply interrupt electron transfer from the N2 terminal cluster to ubiquinone [11] .

 
Acetogenin uvaricin

Another substance blocking complex I is adenosine diphosphate ribose , a in the NADH oxidation reaction. It binds to the enzyme at the nucleotide binding site (FAD) [13] .

The acetogenin family is one of the most potent inhibitors of complex I. These substances have been shown to form chemical crosslinks with the ND2 subunit, which indirectly indicates the role of ND2 in the binding of ubiquinone [14] . It is curious to note that acetogenin rolliniastatin-2 was the first of the discovered inhibitors of complex I, which binds elsewhere than rotenone [15] .

The anti-diabetic drug metformin has a moderate inhibitory effect; apparently, this property of the drug underlies the mechanism of its action [16] .

Succinate dehydrogenase

Main article: Succinate dehydrogenase

Succinate dehydrogenase
 
Identifiers
Code KFno data [ ]

Reaction mechanism

Complex II oxidizes succinate to fumarate and reduces ubiquinone :

Succinate + Q → Fumarate + QH 2

Electrons from succinate are first transferred to FAD, and then through Fe-S clusters to Q. Electron transport in the complex is not accompanied by the generation of a proton gradient . Formed during the oxidation of succinate 2H + remain on the same side of the membrane, that is, in the matrix , and then again absorbed when the quinone is reduced. Thus, complex II does not contribute to the creation of a proton gradient on the membrane and works only as a carrier of electrons from succinate to ubiquinone [17] [18] .

Succinate oxidation
 
The mechanism of oxidation of succinate E2.
 
The mechanism of oxidation of succinate E1cb.

Quite a little is known about the exact mechanism of succinate oxidation. X-ray diffraction analysis revealed that FAD , glutamate -255, arginine -286, and histidine -242 A subunits may be candidates for the deprotonation reaction. There are two possible mechanisms for this elimination (elimination) reaction: E2 and E1cb. In the case of E2, this is an agreed mechanism. The main residues or cofactor deprotonate alpha carbon, and FAD takes the anhydride anion from beta carbon, oxidizing succinate to fumarate . In the case of the E1cb mechanism, the enol form of succinate is formed before FAD adds a hydride anion. In order to determine which mechanism actually takes place, additional succinate dehydrogenase studies are required.

After completion of the reaction, the fumarate , which is weakly bound to the active center of the enzyme, easily dissociates. There are data from which it follows that the cytosolic substrate-binding domain of succinate dehydrogenase undergoes conformational changes: after the product leaves, the enzyme is in open form, and having bound the new substrate, it goes into a closed state, tightly closing around it [19] .

Electron Transfer
 
The mechanism of recovery of ubiquinone.
 
The path of the electron in the respiratory complex II.

As a result of succinate oxidation, its electrons are transferred to FAD , and then transferred along a chain from iron-sulfur clusters from the [Fe-S] cluster to [3Fe-4S]. There, these electrons are transferred to the ubiquinone molecule that is waiting in the binding site.

Ubiquinone Recovery

In the active site, the ubiquinone is stabilized by hydrogen bonds between its carbonyl oxygen atom in the first position and tyrosine -83 subunit D. The transition of electrons to the iron-iron cluster [3Fe-4S] causes the ubiquinone to move to another position. As a result, a second hydrogen bond is formed between the carbonyl group of the ubiquinone in the fourth position and the serine-27 subunit C. After the ubiquinone takes the first electron in the recovery process, it turns into the active radical semiquinone , which, after binding the second electron from the [3Fe-4S] cluster fully restored to ubiquinol [20] .

Heme b

Although the exact function of heme succinate dehydrogenase is still not known, some researchers argue that the first electron entering the ubiquinone via [3Fe-4S] can quickly move back and forth between the heme and the associated ubiquinone. Thus, heme plays the role of electron sink, preventing their interaction with molecular oxygen, which would lead to the formation of reactive oxygen forms .

There is also an assumption that in order not to allow an electron to fall directly from the [3Fe-4S] cluster on a heme, a special gate mechanism is in effect. A likely candidate for the gate is histidine -207 subunit B, which is located directly between the iron-sulfur cluster and heme, not far from the bound ubiquinone, and is likely to control the electron flow between these redox centers [20] .

Inhibitors

There are two classes of inhibitors of complex II: one blocking the pocket for binding succinate, and the other blocking the pocket for binding ubiquinol . The ubiquinol mimic inhibitors include carboxin and thenoyl trifluoroacetone . Synthetic compound malonate as well as components of the Krebs cycle , malate and oxaloacetate belong to inhibitors-analogues of succinate. Interestingly, oxaloacetate is one of the most potent inhibitors of complex II. For some reason, the usual metabolite of the tricarboxylic acid cycle inhibits complex II is not clear, although it is assumed that it can thus play a protective role, minimizing the reverse electron transport in complex I , which results in the formation of superoxide [21] .

Inhibitors that mimic ubiquinol have been used as fungicides in agriculture since the 1960s. For example, carboxin was mainly used for diseases caused by basidiomycetes , such as stem rust and diseases caused by Rhizoctonia . Recently, they were replaced by other compounds with a wider range of suppressed pathogens. These compounds include boscalid , pentiopyrad and fluopyram [22] . Some agriculturally important fungi are not susceptible to the action of this new generation of inhibitors [23] .

Cytochrome-bc 1 complex

Ubiquinol-cytochrome c-oxidoreductase
  The structure of mitochondrial ubiquinol-cytochrome c-oxidoreductase in combination with ubiquinone [24] .
Identifiers
Code KFno data [ ]

Main article: Cytochrome-bc 1 -complex

Cytochrome-bc1-complex ( cytochrome complex bc 1 ) or ubiquinol-cytochrome c-oxidoreductase, or complex III - multiprotein complex of the respiratory electron transport chain and the most important biochemical proton gradient generator on the mitochondrial membrane. This multiprotein transmembrane complex is encoded by the mitochondrial (cytochrome b ) and nuclear genomes [25] .

Complex III was isolated from the mitochondria of the heart of bovine, chicken, rabbit, and yeast mitochondria. It is present in the mitochondria of all animals , plants and all aerobic eukaryotes , as well as on the inner membranes of most eubacteria . It is known that the complex forms a total of 13 protein loops that cross the membrane [25] .

Reaction

 
Schematic illustration of the Q-cycle

Cytochrome- bc 1 -complex oxidizes the reduced ubiquinone and restores cytochrome c (Е ° '= + 0.25 V) according to the equation:

QH 2 + 2 cit. C +3 + 2H + Int → Q + 2 op. with +2 + 4H + out

The electron transport in the complex is associated with proton transfer from the matrix (in) to the intermembrane space (out) and generation of a proton gradient on the mitochondrial membrane. For every two electrons passing through the transfer chain from ubiquinone to cytochrome c , two protons are absorbed from the matrix, and four more are released into the intermembrane space. The reduced cytochrome c moves along the membrane in the aqueous fraction and transfers one electron to the next respiratory complex, cytochrome oxidase [26] [27] .

Q-cycle

The events that take place in this are known as the Q-cycle, which was postulated by Peter Mitchell in 1976. The principle of the Q-cycle is that the transfer of H + through the membrane occurs as a result of the oxidation and reduction of quinones on the complex itself. In this case, quinones, respectively, give and take 2H + from the aqueous phase selectively from different sides of the membrane.

In the structure of complex III there are two centers, or two “pockets” in which quinones can bind. One of them, Q out -center, is located between the 2Fe-2S iron-sulfur cluster and the b L heme near the outer (out) side of the membrane facing the intermembrane space. The recovered ubiquinone (QH 2 ) is bound in this pocket. The other, Q in- pocket, is designed to bind oxidized ubiquinone (Q) and is located near the inner (in) side of the membrane in contact with the matrix.

 
Q-cycle

The first part of the Q-cycle

  1. QH 2 binds to the Q out site, oxidizes to semiquinone (Q •) with the Riske protein-iron center and gives two protons per lumen.
  2. The reduced iron-sulfur center transfers one electron to the plastocyanin via cytochrome c .
  3. Q is linked in the Q in- site.
  4. Q • transfers electrons to cytochrome b heme b L via a low-potential ETC.
  5. Heme b L transfers the electron to b H.
  6. Heme b H restores Q to the state Q •.

The second part of the Q-cycle

  1. The second QH 2 binds to the Q out site of the complex.
  2. Going through a high-potential ETC, one electron restores another plastocyanin. Two more protons enter the lumen.
  3. Through a low-potential ETC, an electron from b H is transferred to Q •, and a fully restored Q 2 - binds two protons of their stroma, turning into QH 2 .
  4. Oxidized Q and reduced QH 2 diffuse into the membrane [28] .

A necessary and paradoxical condition for the Q-cycle is the fact that the life time and the state of semi-quinones in the two binding centers are different. In Q out- center, Q • is unstable and acts as a strong reducing agent capable of giving e to a low-grade heme by. In the Q in- center, a relatively long-lived Q • - is formed , the potential of which allows it to act as an oxidizing agent, accepting electrons from heme b H. Another key moment of the Q-cycle is associated with the divergence of the two electrons entering the complex along two different paths. The study of the crystal structure of the complex showed that the position of the 2Fe-2S center relative to other redox centers can shift. It turned out that the Riske protein has a mobile domain on which the 2Fe-2S cluster is actually located. Taking the electron and recovering, the 2Fe-2S center changes its position, moving away from the Q out- center and heme b L by 17 Å with a turn of 60 ° and thus approaching cytochrome c . Having given the electron to the cytochrome, the 2Fe-2S center, on the contrary, approaches the Q out -center in order to establish closer contact. Thus, a peculiar shuttle (shuttle) is functioning, which guarantees the departure of the second electron to gems b L and b H. So far this is the only example when electron transport in complexes is associated with a mobile domain in the protein structure [29] .

Reactive oxygen species

A small fraction of the electrons leaves the transfer chain before reaching Complex IV . Permanent electron leakage to oxygen leads to the formation of superoxide . This small side reaction leads to the formation of a whole spectrum of reactive oxygen species , which are very toxic and play a significant role in the development of pathologies and aging [30] . Electronic leakage mainly occurs in the Q in- site. This process is facilitated by antimycin A. It blocks gems b in their reduced state, preventing them from dumping electrons on semiquinone Q •, which in turn leads to an increase in its concentration. Semiquinone reacts to oxygen , which leads to the formation of superoxide . The resulting superoxide enters the mitochondrial matrix and the intermembrane space, from where it can enter the cytosol. This fact can be summarized by the fact that Complex III may produce superoxide in the form of uncharged HOO • , which makes it easier to penetrate the outer membrane compared to a charged Superoxide (O 2 -) [31] .


Complex III Inhibitors

All inhibitors of Complex III can be divided into three groups:

  • Antimycin A binds to Q by the intra-site and blocks the transport of electrons from heme b H to the oxidized ubiquinone Q (Q in- site inhibitor).
  • Mixothiazole and stigmetelin bind to the Q external site and block the transfer of an electron from reduced QH 2 to the iron cluster of Riske protein. Both inhibitors bind to Q extr-site, but in different, although overlapping, places.
    • Mixothiazole binds closer to heme b L and is therefore called a “ proximal ” inhibitor.
    • Stigmetelin binds further from heme b L and closer to the Risk protein, with which it interacts.

Some of these substances are used as fungicides (for example, derivatives of strobilurin , the most well-known of which is azoxystrobin , an inhibitor of the Q-site ext ) and antimalarial drugs ( atovaquon ) [1] .

Cytochrome C Oxidase

Main article: Cytochrome c oxidase

Cytochrome c-oxidase
  Cytochrome c-oxidase ox .
Identifiers
Code KFno data [ ]

Cytochrome c oxidase (cytochrome oxidase) or cytochrome c-oxygen oxidoreductase, also known as cytochrome aa 3 and complex IV, is the terminal oxidase of the aerobic respiratory electron transfer chain that catalyzes the transfer of electrons from cytochrome to oxygen to form water [1] . Cytochrome oxidase is present in the inner membrane of the mitochondria of all eukaryotes , where it is called complex IV, as well as in the cell membrane of many aerobic bacteria [32] .

Complex IV sequentially oxidizes four cytochrome C molecules and, taking four electrons, reduces O 2 to H 2 O. When O 2 is reduced, four H + are captured from the mitochondrial matrix to form two H 2 O molecules, and four more H + are actively pumped through the membrane . Thus, cytochrome oxidase contributes to the creation of a proton gradient for the synthesis of ATP and is part of the pathway of oxidative phosphorylation [33] . In addition, this multi-protein complex plays a key role in the regulation of the activity of the entire respiratory chain and the production of energy by a eukaryotic cell [34] .

Reaction

Complex IV cytochrome c oxidase catalyzes the transfer of 4 electrons from 4 molecules of cytochrome to O 2 and pumps 4 protons into the intermembrane space. The complex consists of cytochromes a and a3, which, in addition to heme , contain copper ions .

Oxygen entering the mitochondria from the blood is bound to the iron atom in the cytochrome a3 heme in the form of an O 2 molecule. Each of the oxygen atoms adds two electrons and two protons and turns into a water molecule .

The total reaction catalyzed by the complex is described by the following equation:

4cit. c 2+ + O 2 + 8H + in → 4cit. c 3+ + 2H 2 O + 4H + out

The path of the electron in the complex is known. Cytochrome c binds to subunit II through the mediation of subunits I, III, and VIb and restores the Cu A center located near the surface of the membrane. From the Cu A center, the electron goes to the heme a and then to the binuclear center a 3 -Cu B located in the interior of the membrane. It is in the binuclear center that O 2 is bound and restored to H 2 O [33] . Since oxygen has a high affinity for electrons, in the process of reduction to water, it releases a large amount of free energy . Due to this, aerobic organisms are capable of receiving a much larger amount of energy than can be produced exclusively by anaerobic method.

Oxygen Recovery Mechanism

The mechanism of oxygen reduction has long been the subject of intensive study, but is not clear to the end. The catalytic cycle of cytochrome oxidase consists of six stages, denoted by A (adduct, English Adduct ) [35] , P (peroxy intermediate from English Peroxy intermediate ), F (ferryloxyl intermediate from English Ferryl-oxo intermediate ) [35] , O H (fully oxidized high-energy state from the English Fully-Oxidized High-Energy state ), E (one-electron-reduced state from the English. One-electron reduced state ) and R (restored state from the English. Reduced state ) and so named after the state of the nucleus center [36 ] . It should be noted that the nomenclature of catalytic states is significantly outdated, does not always reflect the real chemical state of the binuclear center, and is preserved in many respects for historical reasons. For example, at stage P, oxygen in the binuclear center is not at all in peroxide form, as it was believed 30 years ago, but in the oxoferryl state, where the bond between the oxygen atoms is already broken [35] . According to modern concepts, the reduction of oxygen in cytochrome c-oxidase occurs by rapid and complete reduction with the pairwise transfer of electrons, which eliminates the formation of reactive oxygen species . The following sequence of events occurs [35] [37] [38] :

 
  • A A fully restored binuclear center quickly binds the O 2 c to the formation of an oxygen adduct, which leads to conformational rearrangements (indicated by thin black arrows).
  • P M There is a rapid transfer of four electrons to oxygen: two are supplied with heme iron a 3 (Fe II → Fe IV ), another located next to Cu B (Cu I → Cu II ), and the fourth comes from the tyrosine residue-244, it also gives the proton needed to break the double O 2 bond. The resulting neutral tyrosine radical is reduced to the anion state by an electron from cytochrome c .
  • P R Protonation of Cu (II) -OH occurs with the formation of a water molecule.
  • F The resulting water molecule binds to the Cu B coordination bond. Iron Fe (IV) = O 2- is reduced to Fe III , and the associated oxygen is protonated. The first water molecule is released.
  • O H The tyrosine anion is protonated, and Cu B is reduced to Cu I by an electron from cytochrome c .
  • E H Iron is reduced to Fe II , after which the OH group bound to it is protonated to form a second water molecule.
  • R In this state, the binuclear center is fully restored and the complex is ready to bind a new oxygen molecule.
Proton Transport Mechanism
 

It is known that eukaryotic cytochrome oxidase transfers through the membrane one proton for each electron obtained from cytochrome c . At one time, the complex pumps one "substrate" proton used to form water through channel K and transfers one additional proton through the membrane through channel D. During one catalytic cycle, the act of translocation falls into four relatively stable stages: P M , F , O H , and E H.
The exact mechanism of proton transport still remains unclear: in recent years, many models have been proposed in which attempts have been made to describe this process in detail [38] . It is not clear how the electron energy is conjugated with the movement of protons. However, in general terms, this can be described as follows [36] :

  1. At the initial stage of the cycle, the proton channels of the complex are closed, then the cytochrome c transfers the electron to the Cu A center.
  2. The electron quickly moves from the Cu A center to heme a , which leads to a change in the redox potential and causes the water molecules in channel D to reorient, making it open to the proton. As a result of the electron moving from Cu A to heme a , the proton moves through channel D and uploads it to the proton loading site PLS ( English proton loading site ).
  3. The electron passes to the binuclear center to heme a 3 , with the result that one substrate proton enters through channel K. In this case, the proton in PLS is experiencing a significant increase in its acidity (from pK = 11 to pK = 5).
  4. At the final stage of the cycle, the proton preloaded in PLS is thrown out, as it is believed, because of the electrostatic repulsion from the substrate proton, which is involved in the reduction of oxygen in the binuclear center.

Inhibitors

Cyanides , sulfides , azides , carbon monoxide and nitrogen monoxide [39] bind to the oxidized or reduced binuclear center of the enzyme and compete with oxygen, inhibiting the enzyme, which leads to cell death from chemical asphyxiation . Methanol , which is a part of technical alcohol , is converted into formic acid in the body, which can also inhibit cytochrome oxidase [40] .

Effect of oxidative potential

Main article: Redox potential

Reducing agentOxidizing agentЕо´, В
H 22 H +- 0,42
OVER • H + H +OVER +- 0.32
NADF • H + H +NADP +- 0.32
Flavoprotein (reconstituted)Flavoprotein (oxidized)- 0.12
Coenzyme Q • H 2Coenzyme Q+ 0.04
Cytochrome B (Fe 2+ )Cytochrome B (Fe 3+ )+ 0.07
Cytochrome C 1 (Fe 2+ )Cytochrome C 1 (Fe 3+ )+ 0.23
Cytochrome A (Fe 2+ )Cytochrome A (Fe 3+ )+ 0.29
Cytochrome A3 (Fe 2+ )Cytochromes A3 (Fe 3+ )+0.55
H 2 O½ o 2+ 0.82

A system with a lower redox potential has a greater ability to donate electrons to a system with more potential. For example, a pair of NAD • H + / NAD + , the redox potential of which is - 0.32 V will donate its electrons to the redox couple flavoprotein (reduced) / flavoprotein (oxidized), which has a greater potential of −0.12 V. The larger redox potential of the redox water / oxygen pair (+0.82 V) indicates that this pair has a very weak ability to donate electrons [41] .

Electron transport chains of bacteria

Bacteria, in contrast to mitochondria, use a large set of electron donors and acceptors, as well as different ways of electron transfer between them. These pathways can be carried out simultaneously, for example, E. coli, when grown on a medium containing glucose as the main source of organic matter, uses two NADH dehydrogenases and two quinoloxidases, which means there are 4 electron transport routes. Most ETC enzymes are inducible and are synthesized only if the path into which they enter is in demand.

Electron donor in addition to organic matter in bacteria can be molecular hydrogen , carbon monoxide , ammonium , nitrite , sulfur , sulfide , divalent iron . Instead, NADH and succinate can be present formate -, lactate -, glyceraldehyde-3-phosphate dehydrogenase, hydrogenase , etc. Instead, oxidases are used in aerobic conditions, in the absence of oxygen the bacteria can be used.. Reductase , regenerating different terminal electron acceptor: fumarate , nitrate- and nitrite reductase , etc.

See also

  • Oxidative phosphorylation
  • NADH-dehydrogenase complex
  • Succinate dehydrogenase
  • Cytochrome-bc 1 complex
  • Cytochrome c oxidase
  • Cell respiration
  • ATP synthase
  • Photosynthesis Electron Transfer Chain
  • Reverse electron transport

Notes

  1. ↑ 1 2 3 JH Holmes, N. Sapeika, H. Zwarenstein. Inhibitory effect of anti-obesity drugs on NADH dehydrogenase of mouse heart homogenates // Research Communications in Chemical Pathology and Pharmacology. - August 1975. - Vol. 11 , no. 4 - S. 645-646 . - ISSN 0034-5164 .
  2. ↑ Rouslan G. Efremov, Rozbeh Baradaran, Leonid A. Sazanov. The architecture of the respiratory complex I (En) // Nature. - 2010/05. - T. 465 , vol. 7297 . - p . 441-445 . - ISSN 1476-4687 . - DOI : 10.1038 / nature09066 .
  3. ↑ Donald Voet, Judith G. Voet. Biochemistry. - Wiley, 2004. - ISBN 047119350X , 9780471193500.
  4. ↑ 1 2 3 4 5 Leonid A. Sazanov. The structure of the respiratory complex I (En) // Nature Reviews Molecular Cell Biology. - 2015/06. - V. 16 , issue. 6 - p . 375-388 . - ISSN 1471-0080 . - DOI : 10.1038 / nrm3997 .
  5. ↑ Rouslan G. Efremov, Leonid A. Sazanov. The coupling mechanism of the respiratory complex I - A structural and evolutionary perspective // Biochimica et Biophysica Acta (BBA) - Bioenergetics. - T. 1817 , vol. 10 - p . 1785-1795 . - DOI : 10.1016 / j.bbabio.2012.02.015 .
  6. ↑ Ulrich Brandt. Energy Converting NADH: Quinone Oxidoreductase (Complex I) // Annual Review of Biochemistry. - 2006-06-01. - T. 75 , no. 1 . - pp . 69-92 . - ISSN 0066-4154 . - DOI : 10.1146 / annurev.biochem.75.103004.142539 .
  7. ↑ Vera G. Grivennikova, Alexander B. Kotlyar, Joel S. Karliner, Gary Cecchini, Andrei D. Vinogradov. Redox-dependent change of the mammalian complex I // Biochemistry. - 2007-09-25. - V. 46 , no. 38 - pp . 10971-10978 . - ISSN 0006-2960 . - DOI : 10.1021 / bi7009822 .
  8. ↑ Ermakov, 2005 , p. 238.
  9. ↑ 1 2 Rozbeh Baradaran, John M. Berrisford, Gurdeep S. Minhas, Leonid A. Sazanov. Crystal structure of the entire respiratory complex I (En) // Nature. - 2013/02. - T. 494 , vol. 7438 . - p . 443-448 . - ISSN 1476-4687 . - DOI : 10.1038 / nature11871 .
  10. ↑ Moretti C., Grenand P. [The "nivrées", or ichthyotoxic plants of French Guyana] (Fr.) // J Ethnopharmacol . - 1988. - September ( v. 6 , No. 2 ). - p . 139-160 . - DOI : 10.1016 / 0378-8741 (82) 90002-2 . - PMID 7132401 .
  11. 2 1 2 Watabe M., Nakaki T. Mitochondrial complex I inhibitor rotenone inhibits and redistributes vesicular monoamine transporter 2 SH-SY5Y cells (eng.) // Molecular Pharmocology: journal. - 2008. - July ( vol. 74 , no. 4 ). - P. 933-940 . - DOI : 10.1124 / mol.108.048546 . - PMID 18599602 .
  12. ↑ Ermakov, 2005 , p. 237.
  13. ↑ Zharova TV, Vinogradov AD. A competitive inhibition of the mitochondrial NADH-ubiquinone oxidoreductase (complex I) by ADP-ribose (English) // Biochimica et Biophysica Acta : journal. - 1997. - July ( vol. 1320 , no. 3 ). - P. 256-264 . - DOI : 10.1016 / S0005-2728 (97) 00029-7 . - PMID 9230920 .
  14. ↑ Nakamaru-Ogiso E., Han H., Matsuno-Yagi A., Keinan E., Sinha SC, Yagi T., Ohnishi T. The ND2 subunit asimicin, a potent complex I inhibitor. (English) // FEBS Letters : journal. - 2010. - January ( vol. 584 , no. 5 ). - P. 883-888 . - DOI : 10.1016 / j.febslet.2010.01.004 . - PMID 20074573 .
  15. ↑ Degli Esposti M., Ghelli A., Ratta M., Cortes D., Estornell E. Natural substances (acetogenins) from the family Annonaceae are powerful inhibitors of mitochondrial NADH dehydrogenase (complex I) (English) // The Biochemical Journal : journal. - 1994. - July ( vol. 301 ). - P. 161-167 . - PMID 8037664 .
  16. ↑ Viollet B., Guigas B., Sanz Garcia N., Leclerc J., Foretz M., Andreelli F. Cellular and molecular mechanisms of metformin: an overview (English) // Clinical Science (London) : journal. - 2012. - March ( vol. 122 , no. 6 ). - P. 253-270 . - DOI : 10.1042 / CS20110386 . - PMID 22117616 .
  17. ↑ Nelson, Cox, 2012 , p. 331-333.
  18. ↑ Ermakov, 2005 , p. 240
  19. ↑ TM Iverson. Catalytic mechanisms of complex II enzymes: A structural perspective // Biochimica et Biophysica Acta (BBA) - Bioenergetics. - T. 1827 , issue. 5 - p . 648-657 . - DOI : 10.1016 / j.bbabio.2012.09.008 .
  20. 2 1 2 Quang M. Tran, Richard A. Rothery, Elena Maklashina, Gary Cecchini, Joel H. Weiner. It is a Responsible Saccharide Binding Site in English. // Journal of Biological Chemistry. - 2006-10-27. - Vol. 281 , iss. 43 . - P. 32310—32317 . - ISSN 1083-351X 0021-9258, 1083-351X . - DOI : 10.1074 / jbc.M607476200 .
  21. ↑ Florian L. Muller, Yuhong Liu, Muhammad A. Abdul-Ghani, Michael S. Lustgarten, Arunabh Bhattacharya. High rates of superoxide production in skeletal-muscle mitochondria respiring for both complex I-complex II-linked substrates // The Biochemical Journal. - 2008-01-15. - T. 409 , vol. 2 - p . 491-499 . - ISSN 1470-8728 . - DOI : 10.1042 / BJ20071162 .
  22. ↑ Hervé F. Avenot, Themis J. Michailides. Dehydrogenase inhibiting (SDHI) fungicides in phytopathogenic fungi // Crop Protection. - T. 29 , vol. 7 - p . 643-651 . - DOI : 10.1016 / j.cropro.2010.02.019 .
  23. ↑ Tiphaine Dubos, Matias Pasquali, Friederike Pogoda, Angèle Casanova, Lucien Hoffmann. Differences between the isopyrazam-sensitive Zymoseptoria tritici and insensitive Fusarium graminearum strains and succinate dehydrogenase sequences // Pesticide Biochemistry and Physiology. - V. 105 , issue. 1 . - pp . 28-35 . - DOI : 10.1016 / j.pestbp.2012.11.004 .
  24. ↑ PDB 1ntz ; Gao X., Wen X., Esser L., Quinn B., Yu.L., Yu.S.A. , Xia D., D.C. complex: a) and inhibitors at the Qi site (Eng.) // Biochemistry: journal. - 2003. - August ( vol. 42 , no. 30 ). - P. 9067-9080 . - DOI : 10.1021 / bi0341814 . - PMID 12885240 .
  25. ↑ 1 2 Ermakov, 2005 , p. 240
  26. ↑ David M. Kramer, Arthur G. Roberts, Florian Muller, Jonathan Cape, Michael K. Bowman. Q-cycle bypass reactions at the cytochrome bc1 (and related) complexes // Methods in Enzymology. - 2004. - T. 382 . - p . 21-45 . - ISSN 0076-6879 . - DOI : 10.1016 / S0076-6879 (04) 82002-0 .
  27. ↑ Antony R. Crofts. The Cytochrome bc1 Complex: Function in the Context of Structure // Annual Review of Physiology. - 2004-02-12. - T. 66 , no. 1 . - p . 689-733 . - ISSN 0066-4278 . - DOI : 10.1146 / annurev.physiol.66.032102.150251 .
  28. ↑ David G. Nicholls, Stuart John Ferguson. Bioenergetics 3. - Gulf Professional Publishing, 2002. - ISBN 0125181213 , 9780125181211.
  29. ↑ Ermakov, 2005 , p. 243.
  30. ↑ Florian L. Muller, Michael S. Lustgarten, Youngmok Jang, Arlan Richardson, Holly Van Remmen. Trends in oxidative aging theories // Free Radical Biology and Medicine. - T. 43 , no. 4 - p . 477–503 . - DOI : 10.1016 / j.freeradbiomed.2007.03.0.034 .
  31. ↑ Florian L. Muller, Yuhong Liu, Holly Van Remmen. Complex III Releases of the Inox Mitochondrial Membrane (Eng.) // Journal of Biological Chemistry. - 2004-11-19. - Vol. 279 , iss. 47 P. P. 49064-49073 . - ISSN 1083-351X 0021-9258, 1083-351X . - DOI : 10.1074 / jbc.M407715200 .
  32. ↑ Elena A. Gorbikova, Ilya Belevich, Mårten Wikström, Michael I. Verkhovsky. The proton donor for OO bond scission by cytochrome c oxidase (Eng.) // Proceedings of the National Academy of Sciences . - National Academy of Sciences , 2008-08-05. - Vol. 105 , iss. 31 . - P. 10733-10737 . - ISSN 1091-6490 0027-8424, 1091-6490 . - DOI : 10.1073 / pnas.0802512105 .
  33. ↑ 1 2 Ermakov, 2005 , p. 244.
  34. ↑ Denis Pierron, Derek E. Wildman, Maik Hüttemann, Gopi Chand Markondapatnaikuni, Siddhesh Aras. Cytochrome c oxidase: Evolution of control via nuclear subunit addition // Biochimica et Biophysica Acta (BBA) - Bioenergetics. - T. 1817 , vol. 4 - p . 590-597 . - DOI : 10.1016 / j.bbabio.2011.07.007 .
  35. ↑ 1 2 3 4 Cytochrome c oxidase: Intermediates of the catalytic cycle and their energy-coupled interconversion (Eng.) // FEBS Letters. - 2012-03-09. - Vol. 586 , iss. 5 - P. 630-639 . - ISSN 0014-5793 . - DOI : 10.1016 / j.febslet.2011.08.037 .
  36. ↑ 1 2 Home Page of the Molecular Biophysics Group (Neopr.) . www.biocenter.helsinki.fi. The appeal date is March 20, 2018.
  37. ↑ Vivek Sharma, Giray Enkavi, Ilpo Vattulainen, Tomasz Róg, Mårten Wikström. Proton-coupled oxidase (Eng.) // Proceedings of the National Academy of Sciences . - National Academy of Sciences , 2015-02-17. - Vol. 112 , iss. 7 - P. 2040-2045 . - ISSN 1091-6490 0027-8424, 1091-6490 . - DOI : 10.1073 / pnas.1409543112 .
  38. ↑ 1 2 Elisa Fadda, Ching-Hsing Yu, Régis Pomès. Electrostatic control of proton pumping in cytochrome with oxidase // Biochimica et Biophysica Acta (BBA) - Bioenergetics. - T. 1777 , vol. 3 - p . 277-284 . - DOI : 10.1016 / j.bbabio.2007.11.0.010 .
  39. ↑ Jose-Ramon Alonso, Francesc Cardellach, Sònia López, Jordi Casademont, Oscar Miró. Carbon monoxide specifically inhibits cytochrome c oxidase of human mitochondrial respiratory chain // Pharmacology & Toxicology. - September 2003. - V. 93 , no. 3 - p . 142-146 . - ISSN 0901-9928 .
  40. ↑ Chris E. Cooper, Guy C. Brown. Carbon monoxide, nitric oxide, hydrogen cyanide and cytochrome oxidative carbon monoxide, nitric oxide, and the mechanism of physiological significance (English) // Journal of Bioenergetics and Biomembranes. - 2008-10-01. - Vol. 40 , iss. 5 - P. 533 . - ISSN 1573-6881 0145-479X, 1573-6881 . - DOI : 10.1007 / s10863-008-9166-6 .
  41. ↑ Korolev A. P., Gridina S. B., Zinkevich E. P. “Fundamentals of biochemistry, part 4: study guide of the Kemerovo Institute of Food Science and Technology” Kemerovo, 2004. - 92s

Literature

  • Plant Physiology / Ed. I.P. Ermakova. - M .: Academy, 2005. - 634 p.
  • Berg, J, Tymoczko, J, and L Stryer. Biochemistry. - 6th. - New York: WH Freeman & Company, 2006. - p. 509–513.
  • David L. Nelson, Michael M. Cox. Fundamentals of biochemistry Leninger. Bioenergy and metabolism = Leninger Principles of Biochemistry. - M .: Bean. Laboratory of Knowledge, 2012. - T. 2. - 692 p. - ISBN 978-5-94774-365-4 .

Links

  • MRC MBU Sazanov group
  • Complex I home page at The Scripps Research Institute
  • MeSH Electron + Transport + Complex + I
  • Instituto Gulbenkian de Ciência & Universidade Nova de Lisboa. Heme-copper oxygen reductases (HCOs) classifier (2009-2010).
  • UMich Orientation of Proteins in Membranes families / superfamily-4
  • MeSH Cytochrome-c + Oxidase
  • cytochrome bc 1 complex site (Antony R. Crofts) at uiuc.edu
  • UMich Orientation of Proteins in Membranes families / superfamily-3
  • MeSH Coenzyme + Q-Cytochrome-c + Reductase
  • Instituto Gulbenkian de Ciência & Universidade Nova de Lisboa. Heme-copper oxygen reductases (HCOs) classifier (2009-2010).
  • UMich Orientation of Proteins in Membranes families / superfamily-4
  • [1] MeSH Cytochrome-c + Oxidase
Source - https://ru.wikipedia.org/w/index.php?title= Respiratory_chain_transfer of electrons&oldid = 100760000


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