Introduction

The body is a complex organism, and as such, it takes energy to maintain proper functioning. Adenosine triphosphate (ATP) is the source of energy for use and storage at the cellular level. The structure of ATP is a nucleoside triphosphate, consisting of a nitrogenous base (adenine), a ribose sugar, and three serially bonded phosphate groups. ATP is commonly referred to as the "energy currency" of the cell, as it provides readily releasable energy in the bond between the second and third phosphate groups. In addition to providing energy, the breakdown of ATP through hydrolysis serves a broad range of cell functions, including signaling and DNA/RNA synthesis. ATP synthesis utilizes energy obtained from multiple catabolic mechanisms, including cellular respiration, beta-oxidation, and ketosis.

The majority of ATP synthesis occurs in cellular respiration within the mitochondrial matrix: generating approximately thirty-two ATP molecules per molecule of glucose that is oxidized. ATP is consumed for energy in processes including ion transport, muscle contraction, nerve impulse propagation, substrate phosphorylation, and chemical synthesis. These processes, as well as others, create a high demand for ATP. As a result, cells within the human body depend upon the hydrolysis of 100 to 150 moles of ATP per day to ensure proper functioning. In the forthcoming sections, ATP will undergo further evaluation of its role as a crucial molecule in the daily functioning of the cell.

Cellular Level

ATP is an excellent energy storage molecule to use as "currency" due to the phosphate groups that link through phosphodiester bonds. These bonds are high energy because of the associated electronegative charges exerting a repelling force between the phosphate groups. A significant quantity of energy remains stored within the phosphate-phosphate bonds. Through metabolic processes, ATP becomes hydrolyzed into ADP, or further to AMP, and free inorganic phosphate groups. The process of ATP hydrolysis to ADP is energetically favorable, yielding Gibbs-free energy of -7.3 cal/mol.[1] ATP must continuously undergo replenishment to fuel the ever-working cell. The routine intracellular concentration of ATP is 1 to 10 uM.[2] Many feedback mechanisms are in place to ensure the maintenance of a consistent ATP level in the cell. The enhancement or inhibition of ATP synthase is a common regulatory mechanism. For example, ATP inhibits phosphofructokinase-1 (PFK1) and pyruvate kinase, two key enzymes in glycolysis, effectively acting as a negative feedback loop to inhibit glucose breakdown when there is sufficient cellular ATP.

Conversely, ADP and AMP can activate PFK1 and pyruvate kinase, serving to promote ATP synthesis in times of high-energy demand. Other systems regulate ATP, such as in the regulatory mechanisms involved in regulating ATP synthesis in the heart. Novel experiments have demonstrated that ten-second bursts called mitochondrial flashes can disrupt ATP production in the heart. During these mitochondrial flashes, the mitochondria release reactive oxygen species and effectively pause ATP synthesis. ATP production inhibition occurs during mitochondrial flashes. During low demand for energy, when heart muscle cells received sufficient building blocks needed to produce ATP, mitochondrial flashes were observed more frequently. Alternatively, when energy demand is high during rapid heart contraction, mitochondrial flashes occurred less often. These results suggested that during times when substantial amounts of ATP are needed, mitochondrial flashes occur less frequently to allow for continued ATP production. Conversely, during times of low energy output, mitochondrial flashes occurred more regularly and inhibited ATP production.[3]

Function

ATP hydrolysis provides the energy needed for many essential processes in organisms and cells. These include intracellular signaling, DNA and RNA synthesis, Purinergic signaling, synaptic signaling, active transport, and muscle contraction. These topics are not an exhaustive list but include some of the vital roles ATP performs.

ATP in Intracellular Signaling

Signal transduction heavily relies on ATP. ATP can serve as a substrate for kinases, the most numerous ATP- binding protein. When a kinase phosphorylates a protein, a signaling cascade can be activated, leading to the modulation of diverse intracellular signaling pathways.[4] Kinase activity is vital to the cell and, therefore, must be tightly regulated. The presence of the magnesium ion helps regulate kinase activity.[5] Regulation is through magnesium ions existing in the cell as a complex with ATP, bound at the phosphate oxygen centers. In addition to kinase activity, ATP can function as a ubiquitous trigger of intracellular messenger release.[6] These messengers include hormones, various-enzymes, lipid mediators, neurotransmitters, nitric oxide, growth factors, and reactive oxygen species.[6] An example of ATP utilization in intracellular signaling can be observed in ATP acting as a substrate for adenylate cyclase. This process mostly occurs in G-protein coupled receptor signaling pathways. Upon binding to adenylate cyclase, ATP converts to cyclic AMP, which assists in signaling the release of calcium from intracellular stores.[7] The cAMP has other roles, including secondary messengers in hormone signaling cascades, activation of protein kinases, and regulating the function of ion channels. 

DNA/RNA Synthesis

DNA and RNA synthesis requires ATP.  ATP is one of four nucleotide-triphosphate monomers that is necessary during RNA synthesis. DNA synthesis uses a similar mechanism, except in DNA synthesis, the ATP first becomes transformed by removing an oxygen atom from the sugar to yield deoxyribonucleotide, dATP.[8]

Purinergic Signaling

Purinergic signaling is a form of extracellular paracrine signaling that is mediated by purine nucleotides, including ATP. This process commonly entails the activation of purinergic receptors on cells within proximity, thereby transducing signals to regulate intracellular processes. ATP is released from vesicular stores and is regulated by IP3 and other common exocytotic regulatory mechanisms. ATP is co-stored and co-released among neurotransmitters, further supporting the notion that ATP is a necessary mediator of purinergic neurotransmission in both sympathetic and parasympathetic nerves. ATP can induce several purinergic responses, including control of autonomic functions, neural glia interactions, pain, and control of vessel tone.[9][10][11][12] 

Neurotransmission

The brain is the highest consumer of ATP in the body, consuming approximately twenty-five percent of the total energy available.[13] A large amount of energy is spent on maintaining ion concentrations for proper neuronal signaling and synaptic transmission.[14] Synaptic transmission is an energy-demanding process. At the presynaptic terminal, ATP is required for establishing ion gradients that shuttle neurotransmitters into vesicles and for priming the vesicles for release through exocytosis.[14]Neuronal signaling depends on the action potential reaching the presynaptic terminal, signaling the release of the loaded vesicles. This process depends on ATP restoring the ion concentration in the axon after each action potential, allowing another signal to occur. Active transport is responsible for resetting the sodium and potassium ion concentrations to baseline values after an action potential occurs through the Na/K ATPase. During this process, one molecule of ATP is hydrolyzed, three sodium ions are transported out of the cell, and two potassium ions are transported back into the cell, both of which move against their concentration gradients.

Action potentials traveling down the axon initiate vesicular release upon reaching the presynaptic terminal. After establishing the ion gradients, the action potentials then propagate down the axon through the depolarization of the axon, sending a signal towards the terminal. Approximately one billion sodium ions are necessary to propagate a single action potential. Neurons will need to hydrolyze nearly one billion ATP molecules to restore the sodium/potassium ion concentration after each cell depolarization.[13]Excitatory synapses largely dominate the grey matter of the brain. Vesicles containing glutamate will be released into the synaptic cleft to activate postsynaptic excitatory glutaminergic receptors. Loading these molecules requires large amounts of ATP due to nearly four thousand glutamate molecules stored into a single vesicle.[13] Significant stores of energy are necessary to initiate the release of the vesicle, drive the glutamatergic postsynaptic processes, and recycle the vesicle as well as the left-over glutamate.[13] Therefore, due to the large amounts of energy required for glutamate packing, mitochondria are close to glutamatergic vesicles.[15]

ATP in Muscle Contraction

Muscle contraction is a necessary function of everyday life and could not occur without ATP. There are three primary roles that ATP performs in the action of muscle contraction. The first is through the generation of force against adjoining actin filaments through the cycling of myosin cross-bridges. The second is the pumping of calcium ions from the myoplasm across the sarcoplasmic reticulum against their concentration gradients using active transport. The third function performed by ATP is the active transport of sodium and potassium ions across the sarcolemma so that calcium ions may be released when the input is received. The hydrolysis of ATP drives each of these processes.[16]

Mechanism

Many processes are capable of producing ATP in the body, depending on the current metabolic conditions. ATP production can occur in the presence of oxygen from cellular respiration, beta-oxidation, ketosis, lipid, and protein catabolism, as well as under anaerobic conditions.

Cellular Respiration

Cellular respiration is the process of catabolizing glucose into acetyl-CoA, producing high-energy electron carriers that will be oxidized during oxidative phosphorylation, yielding ATP. During glycolysis, the first step of cellular respiration, one molecule of glucose breaks down into two pyruvate molecules. During this process, two ATP are produced through substrate phosphorylation by the enzymes PFK1 and pyruvate kinase. There is also the production of two reduced NADH electron carrier molecules. The pyruvate molecules are then oxidized by the pyruvate dehydrogenase complex, forming an acetyl-CoA molecule. The acetyl-CoA molecule is then fully oxidized to yield carbon dioxide and reduced electron carriers in the citric acid cycle. Upon completing the citric acid cycle, the total yield is two molecules of carbon dioxide, one equivalent of ATP, three molecules of NADH, and one molecule of FADH2. These high-energy electron carriers then transfer the electrons to the electron transport chain in which hydrogen ions (protons) are transferred against their gradient into the inner membrane space from the mitochondrial matrix. ATP molecules are then synthesized as protons moving down the electrochemical gradient power ATP synthase.[9] The quantity of ATP produced varies depending on which electron carrier donated the protons. One NADH molecule produces two and a half ATP, whereas one FADH2 molecule produces one and a half ATP molecules.[17]

Beta-Oxidation

Beta-oxidation is another mechanism for ATP synthesis in organisms. During beta-oxidation, fatty acid chains are permanently shortened, yielding Acetyl-CoA molecules. Throughout each cycle of beta-oxidation, the fatty acid is reduced by two carbon lengths, producing one molecule of acetyl-CoA, which can be oxidized in the citric acid cycle, and one molecule each of NADH and FADH2, which transfer their high energy electron to the transport chain.[18]

Ketosis

Ketosis is a reaction that yields ATP through the catabolism of ketone bodies. During ketosis, ketone bodies undergo catabolism to produce energy, generating twenty-two ATP molecules and two GTP molecules per acetoacetate molecule that becomes oxidized in the mitochondria.

Anaerobic Respiration

When oxygen is scarce or unavailable during cellular respiration, cells can undergo anaerobic respiration. During anaerobic conditions, there is a buildup of NADH molecules due to the inability to oxidize NADH to NAD+, limiting the actions of GAPDH and glucose consumption. To maintain homeostatic levels of NADH, pyruvate is reduced to lactate, yielding the oxidation of one NADH molecule in a process known as lactic fermentation. In lactic fermentation, the two molecules of NADH created in glycolysis are oxidized to maintain the NAD+ reservoir. This reaction produces only two molecules of ATP per molecule of glucose. 

Related Testing

Many methods can calculate intracellular ATP levels. A commonly accepted protocol involves using the firefly luciferase, an enzyme that brings about the oxidation of luciferin.[19] This reaction is quantifiable due to the energy output of this reaction, releasing a photon of light, known as bioluminescence, which is quantifiable.

Clinical Significance

ATPs Role in Pain Control

ATP demonstrates a reduction in acute perioperative pain in clinical studies.[20] In these studies, patients received intravenous ATP. The intravenous adenosine infusion acts on the A1 adenosine receptor, initiating a signaling cascade that ultimately aids the pain-relieving effects observed in inflammation. Studies have shown that adenosine compounds decrease allodynia and hyperalgesia when administered in moderate doses.[20] A1 adenosine receptor activation renders effective pain intervention due to delivering a slow onset and a long duration of action, potentially lasting for weeks in some cases.[20]

Anesthesia

ATP supplementation produced positive outcomes during anesthesia. Evidence shows that low doses of adenosine reduce neuropathic pain, ischemic pain, and hyperalgesia to a level comparable to morphine.[21] Adenosine also decreased postoperative opioid usage, suggesting a potential long-lasting A1 adenosine receptor activation.

Cardiology and Surgery

ATP has been demonstrated to be a safe and practical pulmonary vasodilator in patients affected by pulmonary hypertension.[21] Similarly, adenosine and ATP can be employed during surgery to induce hypotension in patients.[21]

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References

1.

Meurer F, Do HT, Sadowski G, Held C. Standard Gibbs energy of metabolic reactions: II. Glucose-6-phosphatase reaction and ATP hydrolysis. Biophys Chem. 2017 Apr;223:30-38. [PubMed: 28282626]

2.

Beis I, Newsholme EA. The contents of adenine nucleotides, phosphagens and some glycolytic intermediates in resting muscles from vertebrates and invertebrates. Biochem J. 1975 Oct;152(1):23-32. [PMC free article: PMC1172435] [PubMed: 1212224]

3.

Wang X, Zhang X, Wu D, Huang Z, Hou T, Jian C, Yu P, Lu F, Zhang R, Sun T, Li J, Qi W, Wang Y, Gao F, Cheng H. Mitochondrial flashes regulate ATP homeostasis in the heart. Elife. 2017 Jul 10;6 [PMC free article: PMC5503511] [PubMed: 28692422]

4.

Mishra NS, Tuteja R, Tuteja N. Signaling through MAP kinase networks in plants. Arch Biochem Biophys. 2006 Aug 01;452(1):55-68. [PubMed: 16806044]

5.

Lin X, Ayrapetov MK, Sun G. Characterization of the interactions between the active site of a protein tyrosine kinase and a divalent metal activator. BMC Biochem. 2005 Nov 23;6:25. [PMC free article: PMC1316873] [PubMed: 16305747]

6.

Zimmermann H. Extracellular ATP and other nucleotides-ubiquitous triggers of intercellular messenger release. Purinergic Signal. 2016 Mar;12(1):25-57. [PMC free article: PMC4749530] [PubMed: 26545760]

7.

Kamenetsky M, Middelhaufe S, Bank EM, Levin LR, Buck J, Steegborn C. Molecular details of cAMP generation in mammalian cells: a tale of two systems. J Mol Biol. 2006 Sep 29;362(4):623-39. [PMC free article: PMC3662476] [PubMed: 16934836]

8.

Joyce CM, Steitz TA. Polymerase structures and function: variations on a theme? J Bacteriol. 1995 Nov;177(22):6321-9. [PMC free article: PMC177480] [PubMed: 7592405]

9.

Bonora M, Patergnani S, Rimessi A, De Marchi E, Suski JM, Bononi A, Giorgi C, Marchi S, Missiroli S, Poletti F, Wieckowski MR, Pinton P. ATP synthesis and storage. Purinergic Signal. 2012 Sep;8(3):343-57. [PMC free article: PMC3360099] [PubMed: 22528680]

10.

Cárdenas C, Miller RA, Smith I, Bui T, Molgó J, Müller M, Vais H, Cheung KH, Yang J, Parker I, Thompson CB, Birnbaum MJ, Hallows KR, Foskett JK. Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. Cell. 2010 Jul 23;142(2):270-83. [PMC free article: PMC2911450] [PubMed: 20655468]

11.

Pablo Huidobro-Toro J, Verónica Donoso M. Sympathetic co-transmission: the coordinated action of ATP and noradrenaline and their modulation by neuropeptide Y in human vascular neuroeffector junctions. Eur J Pharmacol. 2004 Oct 01;500(1-3):27-35. [PubMed: 15464018]

12.

Coco S, Calegari F, Pravettoni E, Pozzi D, Taverna E, Rosa P, Matteoli M, Verderio C. Storage and release of ATP from astrocytes in culture. J Biol Chem. 2003 Jan 10;278(2):1354-62. [PubMed: 12414798]

13.

Attwell D, Laughlin SB. An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab. 2001 Oct;21(10):1133-45. [PubMed: 11598490]

14.

Harris JJ, Jolivet R, Attwell D. Synaptic energy use and supply. Neuron. 2012 Sep 06;75(5):762-77. [PubMed: 22958818]

15.

Wong-Riley MT. Cytochrome oxidase: an endogenous metabolic marker for neuronal activity. Trends Neurosci. 1989 Mar;12(3):94-101. [PubMed: 2469224]

16.

Barclay CJ. Energetics of contraction. Compr Physiol. 2015 Apr;5(2):961-95. [PubMed: 25880520]

17.

Rich PR. The molecular machinery of Keilin's respiratory chain. Biochem Soc Trans. 2003 Dec;31(Pt 6):1095-105. [PubMed: 14641005]

18.

Ronnett GV, Kim EK, Landree LE, Tu Y. Fatty acid metabolism as a target for obesity treatment. Physiol Behav. 2005 May 19;85(1):25-35. [PubMed: 15878185]

19.

Brovko LYu, Romanova NA, Ugarova NN. Bioluminescent assay of bacterial intracellular AMP, ADP, and ATP with the use of a coimmobilized three-enzyme reagent (adenylate kinase, pyruvate kinase, and firefly luciferase). Anal Biochem. 1994 Aug 01;220(2):410-4. [PubMed: 7978286]

20.

Hayashida M, Fukuda K, Fukunaga A. Clinical application of adenosine and ATP for pain control. J Anesth. 2005;19(3):225-35. [PubMed: 16032451]

21.

Agteresch HJ, Dagnelie PC, van den Berg JW, Wilson JH. Adenosine triphosphate: established and potential clinical applications. Drugs. 1999 Aug;58(2):211-32. [PubMed: 10473017]

Disclosure: Jacob Dunn declares no relevant financial relationships with ineligible companies.

Disclosure: Michael Grider declares no relevant financial relationships with ineligible companies.