ATP consists of anadenine attached by the #9-nitrogen atom to the 1′carbonatom of a sugar (ribose), which in turn is attached at the 5' carbon atom of the sugar to a triphosphate group. In its many reactions related to metabolism, the adenine and sugar groups remain unchanged, but the triphosphate is converted to di- and monophosphate, giving respectively the derivativesADP andAMP. The three phosphoryl groups are labeled as alpha (α), beta (β), and, for the terminal phosphate, gamma (γ).[5]
In neutral solution, ionized ATP exists mostly as ATP4−, with a small proportion of ATP3−.[6]
Polyanionic and featuring a potentiallychelating polyphosphate group, ATP binds metal cations with high affinity. Thebinding constant forMg2+ is (9554).[7] The binding of adivalentcation, almost alwaysmagnesium, strongly affects the interaction of ATP with various proteins. Due to the strength of the ATP-Mg2+ interaction, ATP exists in the cell mostly as a complex withMg2+ bonded to the phosphate oxygen centers.[6][8]
A second magnesium ion is critical for ATP binding in the kinase domain.[9] The presence of Mg2+ regulates kinase activity.[10] It is interesting from an RNA world perspective that ATP can carry a Mg ion which catalyzes RNA polymerization.[citation needed]
Salts of ATP can be isolated as colorless solids.[11]
The cycles of synthesis and degradation of ATP; 2 and 1 represent input and output of energy, respectively.
ATP is stable in aqueous solutions betweenpH 6.8 and 7.4 (in the absence of catalysts). At more extreme pH levels, it rapidlyhydrolyses to ADP and phosphate. Living cells maintain the ratio of ATP to ADP at a point ten orders of magnitude from equilibrium, with ATP concentrations fivefold higher than the concentration of ADP.[12][13] In the context of biochemical reactions, the P-O-P bonds are frequently referred to ashigh-energy bonds.[14]
releases 20.5 kilojoules per mole (4.9 kcal/mol) ofenthalpy. This may differ under physiological conditions if the reactant and products are not exactly in these ionization states.[15] The values of the free energy released by cleaving either a phosphate (Pi) or a pyrophosphate (PPi) unit from ATP atstandard state concentrations of 1 mol/L at pH 7 are:[16]
ATP +H 2O → ADP + Pi ΔG°' = −30.5 kJ/mol (−7.3 kcal/mol)
At cytoplasmic conditions, where the ADP/ATP ratio is 10 orders of magnitude from equilibrium, the ΔG is around −57 kJ/mol.[12]
Along with pH, the free energy change of ATP hydrolysis is also associated with Mg2+ concentration, from ΔG°' = −35.7 kJ/mol at a Mg2+ concentration of zero, to ΔG°' = −31 kJ/mol at [Mg2+] = 5 mM. Higher concentrations of Mg2+ decrease free energy released in the reaction due to binding of Mg2+ ions to negatively charged oxygen atoms of ATP at pH 7.[17]
This image shows a 360-degree rotation of a single, gas-phasemagnesium-ATP chelate with a charge of −2. The anion was optimized at the UB3LYP/6-311++G(d,p) theoretical level and the atomic connectivity modified by the human optimizer to reflect the probable electronic structure.
A typical intracellularconcentration of ATP may be 1–10 μmol per gram of tissue in a variety of eukaryotes.[18] The dephosphorylation of ATP and rephosphorylation of ADP and AMP occur repeatedly in the course of aerobic metabolism.[19]
ATP production by a non-photosynthetic aerobic eukaryote occurs mainly in themitochondria, which comprise nearly 25% of the volume of a typical cell.[21]
Glycolysis is viewed as consisting of two phases with five steps each. In phase 1, "the preparatory phase", glucose is converted to 2 d-glyceraldehyde-3-phosphate (g3p). One ATP is invested in Step 1, and another ATP is invested in Step 3. Steps 1 and 3 of glycolysis are referred to as "Priming Steps". In Phase 2, two equivalents of g3p are converted to two pyruvates. In Step 7, two ATP are produced. Also, in Step 10, two further equivalents of ATP are produced. In Steps 7 and 10, ATP is generated from ADP. A net of two ATPs is formed in the glycolysis cycle. The glycolysis pathway is later associated with the Citric Acid Cycle which produces additional equivalents of ATP.[citation needed]
In glycolysis,hexokinase is directly inhibited by its product, glucose-6-phosphate, andpyruvate kinase is inhibited by ATP itself. The main control point for the glycolytic pathway isphosphofructokinase (PFK), which is allosterically inhibited by high concentrations of ATP and activated by high concentrations of AMP. The inhibition of PFK by ATP is unusual since ATP is also a substrate in the reaction catalyzed by PFK; the active form of the enzyme is atetramer that exists in two conformations, only one of which binds the second substrate fructose-6-phosphate (F6P). The protein has twobinding sites for ATP – theactive site is accessible in either protein conformation, but ATP binding to the inhibitor site stabilizes the conformation that binds F6P poorly.[22] A number of other small molecules can compensate for the ATP-induced shift in equilibrium conformation and reactivate PFK, includingcyclic AMP,ammonium ions, inorganic phosphate, and fructose-1,6- and -2,6-biphosphate.[22]
In themitochondrion, pyruvate is oxidized by thepyruvate dehydrogenase complex to theacetyl group, which is fully oxidized to carbon dioxide by thecitric acid cycle (also known as theKrebs cycle). Every "turn" of the citric acid cycle produces two molecules of carbon dioxide, one equivalent of ATPguanosine triphosphate (GTP) throughsubstrate-level phosphorylation catalyzed bysuccinyl-CoA synthetase, as succinyl-CoA is converted to succinate, three equivalents of NADH, and one equivalent ofFADH2. NADH and FADH2 are recycled (to NAD+ andFAD, respectively) byoxidative phosphorylation, generating additional ATP. The oxidation of NADH results in the synthesis of 2–3 equivalents of ATP, and the oxidation of one FADH2 yields between 1–2 equivalents of ATP.[20] The majority of cellular ATP is generated by this process. Although the citric acid cycle itself does not involve molecularoxygen, it is an obligatelyaerobic process because O2 is used to recycle the NADH and FADH2. In the absence of oxygen, the citric acid cycle ceases.[21]
The generation of ATP by the mitochondrion from cytosolic NADH relies on themalate-aspartate shuttle (and to a lesser extent, theglycerol-phosphate shuttle) because the inner mitochondrial membrane is impermeable to NADH and NAD+. Instead of transferring the generated NADH, amalate dehydrogenase enzyme convertsoxaloacetate tomalate, which is translocated to the mitochondrial matrix. Another malate dehydrogenase-catalyzed reaction occurs in the opposite direction, producing oxaloacetate and NADH from the newly transported malate and the mitochondrion's interior store of NAD+. Atransaminase converts the oxaloacetate toaspartate for transport back across the membrane and into the intermembrane space.[21]
In oxidative phosphorylation, the passage of electrons from NADH and FADH2 through the electron transport chain releases the energy to pumpprotons out of the mitochondrial matrix and into the intermembrane space. This pumping generates aproton motive force that is the net effect of a pH gradient and anelectric potential gradient across the inner mitochondrial membrane. Flow of protons down this potential gradient – that is, from the intermembrane space to the matrix – yields ATP by ATP synthase.[23] Three ATP are produced per turn.
Although oxygen consumption appears fundamental for the maintenance of the proton motive force, in the event of oxygen shortage (hypoxia), intracellular acidosis (mediated by enhanced glycolytic rates andATP hydrolysis), contributes to mitochondrial membrane potential and directly drives ATP synthesis.[24]
Most of the ATP synthesized in the mitochondria will be used for cellular processes in the cytosol; thus it must be exported from its site of synthesis in the mitochondrial matrix. ATP outward movement is favored by the membrane's electrochemical potential because the cytosol has a relatively positive charge compared to the relatively negative matrix. For every ATP transported out, it costs 1 H+. Producing one ATP costs about 3 H+. Therefore, making and exporting one ATP requires 4H+. The inner membrane contains anantiporter, the ADP/ATP translocase, which is anintegral membrane protein used to exchange newly synthesized ATP in the matrix for ADP in the intermembrane space.[25]
The citric acid cycle is regulated mainly by the availability of key substrates, particularly the ratio of NAD+ to NADH and the concentrations ofcalcium, inorganic phosphate, ATP, ADP, and AMP.Citrate – the ion that gives its name to the cycle – is a feedback inhibitor ofcitrate synthase and also inhibits PFK, providing a direct link between the regulation of the citric acid cycle and glycolysis.[22]
In the presence of air and various cofactors and enzymes, fatty acids are converted toacetyl-CoA. The pathway is calledbeta-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 FADH2. The acetyl-CoA is metabolized by the citric acid cycle to generate ATP, while the NADH and FADH2 are used by oxidative phosphorylation to generate ATP. Dozens of ATP equivalents are generated by the beta-oxidation of a single long acyl chain.[26]
In oxidative phosphorylation, the key control point is the reaction catalyzed bycytochrome c oxidase, which is regulated by the availability of its substrate – the reduced form ofcytochrome c. The amount of reduced cytochrome c available is directly related to the amounts of other substrates:
which directly implies this equation:
Thus, a high ratio of [NADH] to [NAD+] or a high ratio of [ADP] [Pi] to [ATP] imply a high amount of reduced cytochrome c and a high level of cytochrome c oxidase activity.[22] An additional level of regulation is introduced by the transport rates of ATP and NADH between the mitochondrial matrix and the cytoplasm.[25]
Ketone bodies can be used as fuels, yielding 22 ATP and 2GTP molecules per acetoacetate molecule when oxidized in the mitochondria. Ketone bodies are transported from theliver to other tissues, whereacetoacetate andbeta-hydroxybutyrate can be reconverted to acetyl-CoA to produce reducing equivalents (NADH and FADH2), via the citric acid cycle. Ketone bodies cannot be used as fuel by the liver, because the liver lacks the enzyme β-ketoacyl-CoA transferase, also calledthiolase.Acetoacetate in low concentrations is taken up by the liver and undergoes detoxification through the methylglyoxal pathway which ends with lactate. Acetoacetate in high concentrations is absorbed by cells other than those in the liver and enters a different pathway via1,2-propanediol. Though the pathway follows a different series of steps requiring ATP, 1,2-propanediol can be turned into pyruvate.[27]
C 6H 12O 6 + 2 ADP + 2 Pi → 2 CH 3CH(OH)COOH + 2 ATP + 2 H 2O
Anaerobic respiration is respiration in the absence ofO 2. Prokaryotes can utilize a variety of electron acceptors. These includenitrate,sulfate, and carbon dioxide.
ATP replenishment by nucleoside diphosphate kinases
In plants, ATP is synthesized in thethylakoid membrane of thechloroplast. The process is calledphotophosphorylation. The "machinery" is similar to that in mitochondria except that light energy is used to pump protons across a membrane to produce a proton-motive force. ATP synthase then ensues exactly as in oxidative phosphorylation.[28] Some of the ATP produced in the chloroplasts is consumed in theCalvin cycle, which producestriose sugars.
The total quantity of ATP in the human body is about 0.1 mol/L.[29] The majority of ATP is recycled from ADP by the aforementioned processes. Thus, at any given time, the total amount of ATP + ADP remains fairly constant.
The energy used by human cells in an adult requires the hydrolysis of 100 to 150 mol/L of ATP daily, which means a human will typically use their body weight worth of ATP over the course of the day.[30] Each equivalent of ATP is recycled 1000–1500 times during a single day (150 / 0.1 = 1500),[29] at approximately 9×1020 molecules/s.[29]
ATP is involved insignal transduction by serving as substrate for kinases, enzymes that transfer phosphate groups. Kinases are the most common ATP-binding proteins. They share a small number of common folds.[31]Phosphorylation of a protein by a kinase can activate a cascade such as themitogen-activated protein kinase cascade.[32]
ATP is also a substrate ofadenylate cyclase, most commonly inG protein-coupled receptor signal transduction pathways and is transformed tosecond messenger, cyclic AMP, which is involved in triggering calcium signals by the release of calcium from intracellular stores.[33] This form of signal transduction is particularly important in brain function, although it is involved in the regulation of a multitude of other cellular processes.[34]
ATP is one of four monomers required in the synthesis ofRNA. The process is promoted byRNA polymerases.[35] A similar process occurs in the formation of DNA, except that ATP is first converted to thedeoxyribonucleotide dATP. Like many condensation reactions in nature,DNA replication andDNA transcription also consume ATP.
Aminoacyl-tRNA synthetase enzymes consume ATP in the attachment tRNA to amino acids, forming aminoacyl-tRNA complexes. Aminoacyl transferase binds AMP-amino acid to tRNA. The coupling reaction proceeds in two steps:
The amino acid is coupled to the penultimate nucleotide at the 3′-end of the tRNA (the A in the sequence CCA) via an ester bond (roll over in illustration).
Transporting chemicals out of a cell against a gradient is often associated with ATP hydrolysis. Transport is mediated byATP binding cassette transporters. The human genome encodes 48 ABC transporters, that are used for exporting drugs, lipids, and other compounds.[36]
Cells secrete ATP to communicate with other cells in a process calledpurinergic signalling. ATP serves as aneurotransmitter in many parts of the nervous system, modulates ciliary beating, affects vascular oxygen supply etc. ATP is either secreted directly across the cell membrane through channel proteins[37][38] or is pumped into vesicles[39] which thenfuse with the membrane. Cells detect ATP using thepurinergic receptor proteinsP2X andP2Y.[40] ATP has been shown to be a critically important signalling molecule formicroglia -neuron interactions in the adult brain,[41] as well as during brain development.[42] Furthermore, tissue-injury induced ATP-signalling is a major factor in rapid microglial phenotype changes.[43]
ATP fuelsmuscle contractions.[44] Muscle contractions are regulated by signaling pathways, although differentmuscle types being regulated by specific pathways and stimuli based on their particular function. However, in all muscle types, contraction is performed by the proteinsactin andmyosin.[45]
ATP is initially bound to myosin. WhenATPase hydrolyzes the bound ATP intoADP and inorganicphosphate, myosin is positioned in a way that it can bind to actin. Myosin bound by ADP and Pi forms cross-bridges with actin and the subsequent release of ADP and Pi releases energy as the power stroke. The power stroke causes actin filament to slide past the myosin filament, shortening the muscle and causing a contraction. Another ATP molecule can then bind to myosin, releasing it from actin and allowing this process to repeat.[45][46]
Acetyl phosphate (AcP), a precursor to ATP, can readily be synthesized at modest yields from thioacetate in pH 7 and 20 °C and pH 8 and 50 °C, although acetyl phosphate is less stable in warmer temperatures and alkaline conditions than in cooler and acidic to neutral conditions. It is unable to promote polymerization of ribonucleotides and amino acids and was only capable of phosphorylation of organic compounds. It was shown that it can promote aggregation and stabilization of AMP in the presence of Na+, aggregation of nucleotides could promote polymerization above 75 °C in the absence of Na+. It is possible that polymerization promoted by AcP could occur at mineral surfaces.[49] It was shown that ADP can only be phosphorylated to ATP by AcP and other nucleoside triphosphates were not phosphorylated by AcP. This might explain why all lifeforms use ATP to drive biochemical reactions.[50]
Biochemistry laboratories often usein vitro studies to explore ATP-dependent molecular processes. ATP analogs are also used inX-ray crystallography to determine aprotein structure in complex with ATP, often together with other substrates.[citation needed]
Most useful ATP analogs cannot be hydrolyzed as ATP would be; instead, they trap the enzyme in a structure closely related to the ATP-bound state. Adenosine 5′-(γ-thiotriphosphate) is an extremely common ATP analog in which one of the gamma-phosphate oxygens is replaced by asulfur atom; this anion is hydrolyzed at a dramatically slower rate than ATP itself and functions as an inhibitor of ATP-dependent processes. In crystallographic studies, hydrolysis transition states are modeled by the boundvanadate ion.
Caution is warranted in interpreting the results of experiments using ATP analogs, since some enzymes can hydrolyze them at appreciable rates at high concentration.[51]
The 1997 Nobel Prize in Chemistry was divided, one half jointly toPaul D. Boyer andJohn E. Walker "for their elucidation of the enzymatic mechanism underlying the synthesis of adenosine triphosphate (ATP)" and the other half toJens C. Skou "for the first discovery of an ion-transporting enzyme, Na+, K+ -ATPase."[58]
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