ATP molecule (Adenosine triphosphate)

ATP molecule (Adenosine triphosphate) is an energy stored organic complex that provides energy to countless intracellular biological reactions. In animals, the breakdown of consumed food molecules generates some chemical energy that will be stored in the chemical bonds in the form of ATP. While plants obtain energy from light (photosynthesis) and store it in the form of ATP.

These ATP, further releases energy as fuel to drive the cellular processes including muscle contraction, nerve impulse propagation, biomolecule synthesis (protein, DNA, RNA, amino acids, Lipids, and vitamins), etc.

Interesting point is that ATP provides energy to additional synthesis of ATP during the breakdown of food compound. The breakdown of these food materials occurred by various catalytic enzymes, which use ATP as energy source. Hence, the ATP is often represented as the “molecular unit of currency” of intracellular energy transfer. Majority of ATP molecules produced in cell organelle such as mitochondria by oxidative phosphorylation. However, production levels of ATP will be reduced by uncoupling proteins present on the inner membrane of mitochondria.

Intracellular ATP function

  1. Adenosine triphosphate (ATP) is well-known energy stored molecule that can drive and participate in various intracellular processes.
  2. Kinase is an enzyme, that phosphorylates and activates the biomolecules using intracellular ATP as energy and phosphate source.
  3. Adenylyl cyclase is an enzyme that uses ATP to produce cyclic AMP, which is a second messenger in signal transduction pathway.
  4. ATP can be incorporated into nucleic acids, such as DNA and RNA by polymerases in the process of replication and transcription, respectively.
  5. ATP maintains cellular homeostasis by obtaining energy in one way and, in another way, contributing to cellular energy charge to biological reactions, that results into overall energy balance.
  6. During workout/exercise, intracellular homeostasis depends on the matching of adenosine triphosphate (ATP) availability and ATP demand.
  7. Intracellular ATP can also act as a signaling molecule and opens the potassium channel; that enhances the heart rate.

Extracellular ATP function

  1. ATP also act as a extracellular signaling molecule for specific purinergic receptors to facilitate a wide variety of signaling process including apoptosis, neurotransmission, inflammation, and bone remodeling (or bone metabolism).
  2. Adenosine triphosphate (ATP)-derived activation of inflammasomes can reduce the cancer cell growth.
  3. Adenosine signaling can inhibit the synthesis of several proinflammatory cytokines (TNF-α, IL-6, and IL-8) by lipopolysaccharide -stimulated macrophages and triggers the release of the anti-inflammatory cytokine IL-10.
  4. Extracellular ATP and its metabolite adenosine have also been shown to exert a variety of effects on nearly every cell type in human skin.
  5. ATP can play a direct role in triggering skin inflammatory, regenerative, and fibrotic responses to mechanical injury.
  6. ATP have been shown an indirect role in proliferation of melanocyte and progression of apoptosis.
  7. ATP also show multifaceted role in Langerhans cell-directed adaptive immunity.
  8. Further studies on effect of extracellular ATP in human skin may develop new therapies for skin injury, inflammation, and numerous other cutaneous disorders.
  9. ATP acts as immunosuppressive molecule especially by its metabolite, Adenosine. Scientific findings stated that the conversion of extracellular adenosine triphosphate (ATP) to adenosine by the enzymes ecto-nucleotidases CD39 and CD73 inhibited the functions of innate and adaptive immune cells.
  10. Effects as different as proliferation or differentiation, chemotaxis, release of cytokines or lysosomal constituents, and generation of reactive oxygen or nitrogen species are elicited upon stimulation of blood cells with extracellular ATP.
  11. The extracellular ATP stimulates rapid cell autophagy in monocyte-derived macrophages.
  12. Metabolites play a useful role in communicating the extent of ATP demand to the metabolic supply pathways.

ATP molecule structure

ATP (Adenosine triphosphate) is a nucleotide, that contains adenine (purine base) attached to the first carbon atom of pentose sugar (ribose). While, the fifth carbon atom of the ribose sugar is attached to three phosphate groups by glyosidic bond. These three phosphates are attached by a two phosphodiester bonds, which are esterified higher energy bonds.

Hydrolysis of phosphoanhydride bond present between second and third phosphate groups of ATP molecule generates energy. Once the third phosphate molecule is removed, then the two-phosphate group-containing molecule, ADP will be produced. Similarly, energy will also be released when a second phosphate is removed from ADP to form AMP (adenosine monophosphate). The released free energy will be transferred to other molecules to make unfavorable reactions in a cell to get favorable. AMP can then be recycled into ADP or ATP by gaining a new phosphoanhydride bonds to store energy once again. In the cell, AMP, ADP, and ATP are continuously interconverted as they engage in biological process. Thus, regenerating an ATP from AMP and ADP is essential to balance the energy level of the body; This process allows ATP to store energy like a rechargeable battery for future use.

What are the functions of ATP derived compounds, ADP, AMP, cAMP inside the cell?

The cyclic AMP (cAMP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) are ATP-derived compounds produced in the cell through various mechanisms. However, after production, they have their unique role inside the cell.

1. ADP function

Adenosine diphosphate (ADP) also called as adenosine pyrophosphate (APP). ADP participate in various biological functions, ranging from repairing cell damage to controlling which genes get “turned on” to make their proteins. For instant, ADP in the form of Poly (ADP-ribose) can induces the various mechanism. The breaks in DNA strand activate the enzyme Poly (ADP-ribose) polymerase, that catalyzes the sequential transfer of ADP-ribose units from NAD to nuclear proteins (present on the chromosomes). The resulting poly (ADP-ribose) units unwinds the tightly packed nucleosomal structure of isolated chromatin; thus, induces the DNA repair mechanism (6). Recent findings also stated that the presence of poly (ADP-ribose) can increases the DNA ligase activity; this may enhance the cell capacity to successful completion of DNA repair. Basically, ADP will generate from ATP by losing of a terminal phosphate group, and this process releases energy. ADP also will form by AMP by gaining of one phosphate group, this process require energy.  The conversions between AMP, ADP, and ATP during cellular respiration provides cells with energy, that is needed to carry out cellular activities.

2. AMP function

Adenosine monophosphate (AMP), also known as 5’-adenylic acid, which has only one phosphate group attached to fifth carbon atom of the ribose sugar. This molecule has been found in Ribonucleic acid (RNA) and contains adenine, which is one unit of the genetic code. AMP in the form of RNA act as a messenger molecule to synthesize the proteins. In other forms, like tRNA, rRNA act as translation machinery.

AMP will be produced in two different ways, first, Conversion of two ADP molecules into one ATP and one AMP by the enzyme adenylate kinase. Second, hydrolysis of one high energy phosphodiester bond of ADP will generate AMP. Third, hydrolysis of two phosphodiester bonds of ATP during DNA or RNA polymerization by polymerase, the one molecule of AMP will be produced and incorporated into growing nucleotide chain. It is also produced when RNA is degraded. Later, it can be converted into uric acid, which is a factor of urine, and excreted through the bladder.

3. cAMP function

Cyclic adenosine monophosphate (cAMP) is an intracellular second messenger and involved in many biological signaling pathways. cAMP is produced by the enzyme adenylate cyclase. This enzyme catalyzes the cyclization of ATP (adenosine triphosphate) into cAMP (cyclic adenosine monophosphate), which requires the removal of pyrophosphate (PPi) from ATP. The enzyme adenylate cyclase can be activated by the drug forskolin found in roots of Coleus forskohlii.

The produced cAMP relay the various signals to transcription factors and modulates the gene expression. cAMP signals can reduce the inflammation and controls the blood pressure. cAMP prevents platelet aggregation. Signal from this messenger shows positive inotropic action in the heart and shows anti glaucoma effects. cyclic AMP activates target enzymes (e.g. protein kinase A) in the cells and opens ion channels in the cell membrane, this results into muscle relaxation and bronchodilation.

 

Scientific study and clinical correlations

1. Studies on extracellular ATP

The extracellular levels of Adenosine triphosphate (ATP) will be increased in response to tissue damage and cellular stress; these extracellular ATP enhances tissue repair, promotes the recruitment of immune phagocytes and dendritic cells, and acts as a co-activator of NLR family, pyrin domain-containing 3 (NLRP3) inflammasomes through activating the P2X and P2Y receptors. However, conversion of extracellular ATP to adenosine, essentially through the enzymatic activity of the ecto-nucleotidases CD39 and CD73; acts as a negative-feedback mechanism to prevent excessive immune responses.

The anti-inflammatory activity of adenosine in lugs shown to be reduced the severity of asthma. These findings are nowadays encouraging the scientist to analyze the adenosine analogues to reduce the risk of this disease.

The increased adenosine triphosphate (ATP) levels in erythrocytes from patients with chronic renal failure (CRF) has been observed in many studies but the mechanism involved in these abnormalities still is controversial.

The conserved functions of purinergic receptors and their ubiquitous expression in different tissues suggest that ATP and adenosine receptors may be implicated in the motility of other cell types, including tumor cells.

2. Studies on intracellular ATP

Activation of K+ channel IKs enhances the heart function and reduce the rate of heart failure. Scientific findings said that at physiological concentrations, intracellular ATP can act as a signaling molecule to activate the slowly activating K+ channel IKs it results into regulation of heart rate adaptation. The binding of intracellular ATP molecule to the pore-forming α-subunit of IKs, KCNQ1 (channel), stimulated the channel to open. Congenital mutations in the channel protein reduced the ATP binding or subsequent opening of the IKs channel, these abnormality conditions are related to cardiac arrhythmias in human patients. Abnormalities in electrical signals are often associated with fatality in cardiovascular diseases, including ischemia and heart failure, in these conditions, cardiac cells have low ATP levels. This finding stated that increasing intracellular ATP levels in patient with cardiovascular diseases a new possibility to manage the diseases, and the ATP site provides a unique target for therapies (Yang et al., 2013).

ATP metabolite, adenosine as a signaling molecule

The extracellular adenosine molecule will play both agonistic and antagonistic activity in tumor cells, which is strictly based on activation of specific receptor.

  1. Positive role: The extracellular adenosine and its synthetic drug N6-cyclopentyladenosine (CPA) can significantly decreases the tumor size by activating the adenosine A1 receptor (A1AR).
  2. Negative role: Studies found that Adenosine can also protect tumor cells from Immune destruction by activating the adenosine A2A receptor (A2AAR), which is agonist receptor in cancer cells. Adenosine can also protect tissues against the negative consequences of hypoxia or ischemia.

Due to higher negative role of adenosine in tumor cells, finally, scientists after various studies stated that enhancement of extracellular ATP can activate the inflammasomes, that result in to induced anticancer activity. While, by inhibiting the extracellular accumulation of adenosine in tumor cells, can reduced the growth of tumor or induce the anticancer activity to minimize the dose of anticancer drugs.

Phosphorus cycle

Since ATP is a Nature’s universal energy currency, recycling of phosphorus (major element of ATP) is crucial process to maintain the phosphorus levels in the living organisms. Extraction of phosphorus from dead animals and plants and development of phosphorus-containing fertilizers are established to regulated the phosphorus levels. The phosphorus present in the soil and fertilizers is utilized by plants to produce their own ATP. When we consume the plant related foods, then we metabolize their phosphorus and synthesize our own ATP. When we expire, our phosphorus goes back into the environment to begin the cycle again.

 

 Data source:

  1. Bar-Yehuda, M. Synowitz, J.D. Powell, K.N. Klotz, S. Gessi, and P.A. Borea. Adenosine Receptors and Cancer. Handb Exp Pharmacol. 2009; (193): 399–441.doi: [10.1007/978-3-540-89615-9_14] (ATP)
  2. J Stagg & M J Smyth. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 29(39):5346-58 · September 2010. DOI: 10.1038/onc.2010.292.
  3. Aton M. Holzer, Richard D. Granstein. Role of Extracellular Adenosine Triphosphate in Human Skin. org/10.1177/120347540400800203.
  4. Simonetta Falzoni, Giovanna Donvito, Francesco Di Virgilio. Detecting adenosine triphosphate in the pericellular space. The royal socileity, Published 23 April 2013.DOI: 10.1098/rsfs.2012.0101.
  5. Yang Li, Junyuan Gao, Zhongju Lu, Kelli McFarland, Jingyi Shi, Kevin Bock, Ira S. Cohen, and Jianmin Cui. Intracellular ATP binding is required to activate the slowly activating K+ channel IKs. PNAS Nov, 19, 2013 110 (47) 18922-18927.
  6. Berger NA. Poly(ADP-ribose) in the cellular response to DNA damage.Radiat Res. 1985 Jan;101(1):4-15
  7. Verena Katharina Raker, Christian Becker, and Kerstin Steinbrink. The cAMP Pathway as Therapeutic Target in Autoimmune and Inflammatory Diseases. Immunol., 31 March 2016.
  8. Tesmer JJ, Sunahara RK, Gilman AG, Sprang SR. Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS. Science. 1997 Dec 12;278(5345):1907-16. PMID:9417641
  9. Linder JU, Schultz A, Schultz JE. Adenylyl cyclase Rv1264 from Mycobacterium tuberculosis has an autoinhibitory N-terminal domain. J Biol Chem. 2002 May 3;277(18):15271-6. Epub 2002 Feb 11. PMID:11839758doi:1074/jbc.M200235200.
  10. Rickman L, Scott C, Hunt DM, Hutchinson T, Menendez MC, Whalan R, Hinds J, Colston MJ, Green J, Buxton RS. A member of the cAMP receptor protein family of transcription regulators in Mycobacterium tuberculosis is required for virulence in mice and controls transcription of the rpfA gene coding for a resuscitation promoting factor. Mol Microbiol. 2005 Jun;56(5):1274-86. PMID:doi:1111/j.1365-958.2005.04609.x

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