The electron transport chain is a series of four protein complexes that couple redox reactions, creating an electrochemical gradient that leads to the creation of ATP in a complete system named oxidative phosphorylation. It occurs in mitochondria in both cellular respiration and photosynthesis. In the former, the electrons come from breaking down organic molecules, and energy is released. In the latter, the electrons enter the chain after being excited by light, and the energy released is used to build carbohydrates.
Aerobic cellular respiration is made up of three parts: glycolysis, the citric acid (Krebs) cycle, and oxidative phosphorylation. In glycolysis, glucose metabolizes into two molecules of pyruvate, with an output of ATP and nicotinamide adenine dinucleotide (NADH). Each pyruvate oxidizes into acetyl CoA and an additional molecule of NADH and carbon dioxide (CO2). The acetyl CoA is then used in the citric acid cycle, which is a chain of chemical reactions that produce CO2, NADH, flavin adenine dinucleotide (FADH2), and ATP. In the final step, the three NADH and one FADH2 amassed from the previous steps are used in oxidative phosphorylation, to make water and ATP.
Oxidative phosphorylation has two parts: the electron transport chain (ETC) and chemiosmosis. The ETC is a collection of proteins bound to the inner mitochondrial membrane and organic molecules, which electrons pass through in a series of redox reactions, and release energy. The energy released forms a proton gradient, which is used in chemiosmosis to make a large amount of ATP by the protein ATP-synthase.
Photosynthesis is a metabolic process that converts light energy into chemical energy to build sugars. In the light-dependent reactions, light energy and water are used to make ATP, NADPH, and oxygen (O2). The proton gradient used to make the ATP forms via an electron transport chain. In the light-independent reactions, sugar is made from the ATP and NADPH from the previous reactions.
In the electron transport chain (ETC), the electrons go through a chain of proteins that increases its reduction potential and causes a release in energy. Most of this energy is dissipated as heat or utilized to pump hydrogen ions (H+) from the mitochondrial matrix to the intermembrane space and create a proton gradient. This gradient increases the acidity in the intermembrane space and creates an electrical difference with a positive charge outside and a negative charge inside. The ETC proteins in a general order are complex I, complex II, coenzyme Q, complex III, cytochrome C, and complex IV.
ATP synthase, also called complex V, uses the ETC generated proton gradient across the inner mitochondrial membrane to form ATP. ATP-synthase contains up of F0 and F1 subunits, which act as a rotational motor system. F0 is hydrophobic and embedded in the inner mitochondrial membrane. It contains a proton corridor that is protonated and deprotonated repeatedly as H+ ions flow down the gradient from intermembrane space to matrix. The alternating ionization of F0 causes rotation, which alters the orientation of the F1 subunits. F1 is hydrophilic and faces the mitochondrial matrix. Conformational changes in F1 subunits catalyze the formation of ATP from ADP and Pi. For every 4 H+ ions, 1 ATP is produced. ATP-synthase can also be forced to run in reverse, consuming ATP to produce a hydrogen gradient, as is seen in some bacteria.[15][16][17]
Nicotinamide adenine dinucleotide has two forms: NAD+ (oxidized) and NADH (reduced). It is a dinucleotide connected by phosphate groups. One nucleoside has an adenine base and the other nicotinamide. When involved in metabolic redox reactions, the mechanism is as shown in Reaction 1.
R is the reactant, for example, sugar.
NADH enters the ETC at complex I and produces a total of 10 H+ ions through the ETC (4 from complex I, 4 from complex III, and 2 from complex IV). ATP-synthase synthesizes 1 ATP for 4 H+ ions. Therefore, 1 NADH = 10 H+, and 10/4 H+ per ATP = 2.5 ATP per NADH (**some sources round up**). When NADH is oxidized, it breaks into NAD+, H+, and 2 e- as shown in Reaction 2.
Flavin adenine dinucleotide has 4 redox states, 3 of them being FAD (quinone, fully oxidized form), FADH- (semiquinone, partially oxidized), and FADH2 (hydroquinone, fully reduced). FAD is made up of an adenine nucleotide and a flavin mononucleotide (FMN), connected by phosphate groups. FMN is synthesized in part from vitamin B2 (riboflavin). FAD contains a highly stable aromatic ring, and FADH2 does not. When FADH2 oxidizes, it becomes aromatic and releases energy, as seen in Reaction 3. This state makes FAD a potent oxidizing agent, with an even more positive reduction potential than NAD. FADH2 enters the ETC at complex II and creates a total of 1.5 ATP (4 H+ from complex III, and 2 H+ from complex IV; 6/4 H+ per ATP = 1.5 ATP per FADH2 **some sources round up**).[18]
FAD also functions in several metabolic pathways outside of the ETC, including DNA repair (MTHF repair of UV damage), fatty acid beta-oxidation (acyl-CoA dehydrogenase), and synthesis of coenzymes (CoA, CoQ, heme).
Uncoupling Agents
An uncoupling agent dissociates the electron transport chain from phosphorylation by ATP-synthase, preventing the formation of ATP. Disruption of the phospholipid bilayer of membranes causes a fluid-like and disorganized state, which allows protons to flow through more freely. This proton leak weakens the electrochemical gradient, while also transferring protons without the use of ATP-synthase such that no ATP is produced.
While the cell becomes starved of ATP, the ETC will overwork in an attempt to shuttle more and more electrons to ATP-synthase without success. The ETC regularly produces heat as the electrons transfer from one carrier to the next, and this overactivity will raise the body temperature as a result. Additionally, cells will adapt to utilizing fermentation as if in anaerobic conditions; this may cause a type B lactic acidosis in affected patients.[19]
Aspirin (Salicylic Acid)
Thermogenin
Oxidative Phosphorylation Inhibitors
Certain poisons can inhibit cellular oxidative phosphorylation such as rotenone, carboxin, antimycin A, cyanide, carbon monoxide (CO), sodium azide, and oligomycin. Rotenone inhibits complex I, carboxin inhibits complex II, antimycin A inhibits complex III, and cyanide and CO inhibit complex IV. Oligomycin inhibits ATP synthase.[23][24]
Rotenone (and some barbiturates) – inhibits complex I (coenzyme Q binding site)
Carboxin – inhibits complex II (coenzyme Q binding site)
Doxorubicin – coenzyme Q (theoretical)
Antimycin A – inhibits complex III (cytochrome c reductase)
Carbon Monoxide (CO) – inhibits complex IV (cytochrome c oxidase)
Cyanide (CN) – inhibits complex IV (cytochrome c oxidase)
Oligomycin – inhibits ATP-synthase (complex V)
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