Instruct: Given a question, retrieve passages that answer the question.
Query: How long have we known about oxidative phosphorylation?
The field of oxidative phosphorylation began with the report in 1906 by Arthur Harden of a vital role for phosphate in cellular fermentation, but initially only sugar phosphates were known to be involved.[94] However, in the early 1940s, the link between the oxidation of sugars and the generation of ATP was firmly established by Herman Kalckar,[95] confirming the central role of ATP in energy transfer that had been proposed by Fritz Albert Lipmann in 1941.[96] 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.[97] The term oxidative phosphorylation was coined by Volodymyr Belitser in 1939.[98][99]
Kalckar was fortunate to be working at an important period in biochemistry's evolution. The biochemical community was in the process of demonstrating the chemical reactions involved in breakdown of foodstuffs essential for growth. At the same time, physiologists were demonstrating the involvement of some of these reactions various physiological processes, e.g. muscle contraction. Kalckar's breakthrough work was the demonstration that organic compounds, which were phosphorylated during metabolic processes, involved oxygen consumption; oxygen consumption was linked to organic compound phosphorylation. His key experiment demonstrated that in frog muscles where glycolysis had been inhibited with iodoacetate, muscular contraction continued for a short period using phosphocreatine as a source of energy. Kalckar referred to this process as “aerobic phosphorylation” (now called oxidative phosphorylation, a biochemical process fundamental to all living organisms). The work was the first demonstration that carbohydrate oxidation and carbohydrate phosphorylation were linked, i.e. the two pathways were directly “coupled.” Furthermore, the study helped establish the basic phenomenon of oxidative phosphorylation, opened the way for its systematic exploration, and suggested for the first time that phosphate compounds acted as a link between catabolism and anabolism.
Oxidative phosphorylation (UK /ɒkˈsɪd.ə.tɪv/, US /ˈɑːk.sɪˌdeɪ.tɪv/)[1] is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing energy which is used to produce adenosine triphosphate (ATP). In most eukaryotes, this takes place inside mitochondria. Almost all aerobic organisms carry out oxidative phosphorylation. This pathway is probably so pervasive because it is a highly efficient way of releasing energy, compared to alternative fermentation processes such as anaerobic glycolysis.
Post-translational modifications of prolidase regulate its enzymatic abilities. Phosphorylation of prolidase has been shown to increase its activity while dephosphorylation leads to a decrease in enzyme activity. Analysis of known consensus sequence required for serine/threonine phosphorylation revealed that prolidase contains at least three potential sites for serine/threonine phosphorylation. Nitric oxide, both exogenously acquired and endogenously generated, was shown to increase prolidase activity in a time- and dose-dependent manner via phosphorylation at these serine and threonine sites. Additionally, prolidase may also be regulated at tyrosine phosphorylation sites, which are mediated by FAK and MAPK signaling pathways.
Oxidative phosphorylation produces 26 of the 30 equivalents of ATP generated in cellular respiration by transferring electrons from NADH or FADH2 to O2 through electron carriers. The energy released when electrons are passed from higher-energy NADH or FADH2 to the lower-energy O2 is required to phosphorylate ADP and once again generate ATP. It is this energy coupling and phosphorylation of ADP to ATP that gives the electron transport chain the name oxidative phosphorylation. 
High amount of aerobic glycolysis (also known as the Warburg effect) distinguishes cancer cells from normal cells. The conversion of glucose to lactate rather than metabolizing it in the mitochondria through oxidative phosphorylation, (which can also occur in hypoxic normal cells) persists in malignant tumor despite the presence of oxygen. This process normally inhibits glycolysis which is also known as Pasteur effect. One of the reasons it is observed is because of the malfunction of mitochondria. Although ATP production by glycolysis can be more rapid than by oxidative phosphorylation, it is far less efficient in terms of ATP generated per unit of glucose consumed. Rather than oxidizing glucose for ATP production, glucose in cancer cells tends to be used for anabolic processes, such as ribose production, protein glycosylation and serine synthesis. This shift therefore demands that tumor cells implement an abnormally high rate of glucose uptake to meet their increased needs.
Several alternative theories of carcinogenesis, however, are based on scientific evidence and are increasingly being acknowledged. Some researchers believe that cancer may be caused by aneuploidy (numerical and structural abnormalities in chromosomes) rather than by mutations or epimutations. Cancer has also been considered as a metabolic disease in which the cellular metabolism of oxygen is diverted from the pathway that generates energy (oxidative phosphorylation) to the pathway that generates reactive oxygen species (figure). This causes an energy switch from oxidative phosphorylation to aerobic glycolysis (Warburg's hypothesis) and the accumulation of reactive oxygen species leading to oxidative stress (oxidative stress theory of cancer). All these theories of carcinogenesis may be complementary rather than contradictory. Aberrant DNA methylation patterns – hypermethylation and hypomethylation compared to normal tissue – have been associated with a large number of human malignancies. (See DNA methylation in cancer)
Mutations in "FARS2" have been associated to combined oxidative phosphorylation deficiency 14, spastic paraplegia 77, and infantile-onset epilepsy and cytochrome c oxidase deficiency. Both combined oxidative phosphorylation deficiency 14 and spastic paraplegia 77 are autosomal recessive in nature and have been linked to several pathogenic variants including Y144C, I329T, D391V, and D142Y. Combined oxidative phosphorylation deficiency 14 is characterized by neonatal onset of global developmental delay, refractory seizures, lactic acidosis, and deficiencies of multiple mitochondrial respiratory enzymes. Spastic paraplegia, meanwhile, is a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs, with patients often exhibiting difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. One case of infantile-onset epilepsy and cytochrome c oxidase deficiency resulting from a "FARS2" Asp325Tyr missense mutation has also been reported. Early-onset epilepsy, neurological deficits, and complex IV deficiency are the main characteristics of the disease stemming from this mutation.
ATP can be produced by a number of distinct cellular processes; the three main pathways in eukaryotes are (1) glycolysis, (2) the citric acid cycle/oxidative phosphorylation, and (3) beta-oxidation. The overall process of oxidizing glucose to carbon dioxide, the combination of pathways 1 and 2, is known as cellular respiration, produces about 30 equivalents of ATP from each molecule of glucose.
Phosphorylation of AMPARs can regulate channel localization, conductance, and open probability. GluA1 has four known phosphorylation sites at serine 818 (S818), S831, threonine 840, and S845 (other subunits have similar phosphorylation sites, but GluR1 has been the most extensively studied). S818 is phosphorylated by protein kinase C, and is necessary for long-term potentiation (LTP; for GluA1's role in LTP, see below). S831 is phosphorylated by CaMKII and PKC during LTP, which helps deliver GluA1-containing AMPAR to the synapse, and increases their single channel conductance. The T840 site was more recently discovered, and has been implicated in LTD. Finally, S845 is phosphorylated by PKA which regulates its open probability.
One of the effects of exercise is an increase in fatty acid metabolism, which provides more energy for the cell. One of the key pathways in AMPK’s regulation of fatty acid oxidation is the phosphorylation and inactivation of acetyl-CoA carboxylase. Acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl-CoA, an inhibitor of carnitine palmitoyltransferase 1 (CPT-1). CPT-1 transports fatty acids into the mitochondria for oxidation. Inactivation of ACC, therefore, results in increased fatty acid transport and subsequent oxidation. It is also thought that the decrease in malonyl-CoA occurs as a result of malonyl-CoA decarboxylase (MCD), which may be regulated by AMPK. MCD is an antagonist to ACC, decarboxylating malonyl-CoA to acetyl-CoA, resulting in decreased malonyl-CoA and increased CPT-1 and fatty acid oxidation.
AMPK also plays an important role in lipid metabolism in the liver. It has long been known that hepatic ACC has been regulated in the liver by phosphorylation. AMPK also phosphorylates and inactivates 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a key enzyme in cholesterol synthesis. HMGR converts 3-hydroxy-3-methylglutaryl-CoA, which is made from acetyl-CoA, into mevalonic acid, which then travels down several more metabolic steps to become cholesterol. AMPK, therefore, helps regulate fatty acid oxidation and cholesterol synthesis.
Not all inhibitors of oxidative phosphorylation are toxins. In brown adipose tissue, regulated proton channels called uncoupling proteins can uncouple respiration from ATP synthesis.[92] This rapid respiration produces heat, and is particularly important as a way of maintaining body temperature for hibernating animals, although these proteins may also have a more general function in cells' responses to stress.[93]
In the mitochondrion, pyruvate is oxidized by the pyruvate dehydrogenase complex to the acetyl group, which is fully oxidized to carbon dioxide by the citric acid cycle (also known as the Krebs cycle). Every "turn" of the citric acid cycle produces two molecules of carbon dioxide, one equivalent of ATP guanosine triphosphate (GTP) through substrate-level phosphorylation catalyzed by succinyl-CoA synthetase, as succinyl- CoA is converted to Succinate, three equivalents of NADH, and one equivalent of FADH. NADH and FADH are recycled (to NAD and FAD, respectively), generating additional ATP by oxidative phosphorylation. The oxidation of NADH results in the synthesis of 2–3 equivalents of ATP, and the oxidation of one FADH yields between 1–2 equivalents of ATP. The majority of cellular ATP is generated by this process. Although the citric acid cycle itself does not involve molecular oxygen, it is an obligately aerobic process because O is used to recycle the NADH and FADH. In the absence of oxygen, the citric acid cycle ceases.
By controlling the amount of available reducing equivalents generated by the Krebs cycle, Oxoglutarate dehydrogenase has a downstream regulatory effect on oxidative phosphorylation and ATP production. Reducing equivalents (such as NAD+/NADH) supply the electrons that run through the electron transport chain of oxidative phosphorylation. Increased Oxoglutarate dehydrogenase activation levels serve to increase the concentrations of NADH relative to NAD+. High NADH concentrations stimulate an increase in flux through oxidative phosphorylation.
Phosphine oxides are phosphorus compounds with the formula OPX. When X = alkyl or aryl, these are organophosphine oxides. Triphenylphosphine oxide is an example. An inorganic phosphine oxide is phosphoryl chloride (POCl). Such compounds are thermally stable, decomposing only above 450 °C. Phosphoryl refers to a functional group drawn with a phosphorus-oxygen double bond.
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,[5] 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.[6]
When asked in later life about her most exciting moments in science, Cohn replied: "In 1958, using nuclear magnetic resonance, I saw the first three peaks of ATP. That was exciting. [I could] distinguish the three phosphorus atoms of ATP with a spectroscopic method, which had never been done before." Using radioisotope of oxygen, Cohn discovered how phosphorylation and water are part of the electron transport system of the metabolic pathway oxidative phosphorylation, the ubiquitous process used by all aerobic organisms to generate energy, in the form of ATP, from nutrients. She elucidated how the divalent metal ions are involved in the enzymatic reactions of ADP and ATP by studying NMR spectra of the phosphorus nuclei and the structural change in the presence of various divalent ions.
The amino acid methionine is prone to oxidation, but oxidized methionine can be reversible. Oxidation of methionine is shown to inhibit the phosphorylation of adjacent Ser/Thr/Tyr sites in proteins. This gives a plausible mechanism for cells to couple oxidative stress signals with cellular mainstream signaling such as phosphorylation.
Oligomycin A is an inhibitor of ATP synthase. In oxidative phosphorylation research, it is used to prevent state 3 (phosphorylating) respiration. Oligomycin A inhibits ATP synthase by blocking its proton channel (Fo subunit), which is necessary for oxidative phosphorylation of ADP to ATP (energy production). The inhibition of ATP synthesis by oligomycin A will significantly reduce electron flow through the electron transport chain; however, electron flow is not stopped completely due to a process known as "proton leak" or "mitochondrial uncoupling". This process is due to facilitated diffusion of protons into the mitochondrial matrix through an uncoupling protein such as thermogenin, or UCP1.
Rck-2 is a gene that plays a major role in clock control of translation. Rck-2 protein is a kinase and is rhythmically activated through phosphorylation events based on the periodicity of the clock. Rck-2 activation is directly associated with the phosphorylation of eEF-2, which is an elongation factor that plays a major role in translation. Phosphorylation of eEF-2 has an inhibitory effect on the activity of translation. Rck-2 is largely studied in "Neurospora crassa" but has significant homology to humans. Knockout strains have been produced in the model organism "N. crassa" but there are no human pathologies associated with its deletion. While the basic mechanisms of circadian transcriptional control are known, little is understood about how the clock controls mRNA translation, which makes the characterization of pathways responsible for translational control all the more important.
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.[58] In E. coli, for example, oxidative phosphorylation can be driven by a large number of pairs of reducing agents and oxidizing agents, which are listed below. The midpoint potential of a chemical measures how much energy is released when it is oxidized or reduced, with reducing agents having negative potentials and oxidizing agents positive potentials.
The anhydride phosphoryl difluoride oxide (POF) reacts with oxides such as UO to yield difuorophosphates. Phosphoryl difluoride oxide also reacts with alkali fluorides to yield difluorophosphates.
In the presence of air and various cofactors and enzymes, fatty acids are converted to acetyl-CoA. The pathway is called beta-oxidation. Each cycle of beta-oxidation shortens the fatty acid chain by two carbon atoms and produces one equivalent each of acetyl-CoA, NADH, and FADH. The acetyl-CoA is metabolized by the citric acid cycle to generate ATP, while the NADH and FADH are used by oxidative phosphorylation to generate ATP. Dozens of ATP equivalents are generated by the beta-oxidation of a single long acyl chain. 
There are several well-known drugs and toxins 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.[87] As a result, the proton pumps are unable to operate, as the gradient becomes too strong for them to overcome. NADH is then no longer oxidized and the citric acid cycle ceases to operate because the concentration of NAD+ falls below the concentration that these enzymes can use.
The encoded protein (PHC) catalyzes the transport of phosphate from the cytosol into the mitochondrial matrix, either by proton cotransport or in exchange for hydroxyl ions. In the final steps of oxidative phosphorylation, this protein catalyzes the uptake of a phosphate ion with a proton across the mitochondrial inner membrane. The availability of inorganic phosphate for oxidative phosphorylation is mainly dependent on PHC activity. To substantially affect oxidative phosphorylation, PHC depletion must be severe, exceeding 85%. This protein may be involved in regulation of the mitochondrial permeability transition pore (mPTP). 