Deoxyadenosine triphosphate (dATP) is a

nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecule ...

used in cells for

DNA synthesis DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occurs ...

(or replication), as a substrate of

DNA polymerase A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create ...

. It is classified as a purine nucleoside triphosphate, with its chemical structure consisting of a

deoxyribose Deoxyribose, or more precisely 2-deoxyribose, is a monosaccharide with idealized formula H−(C=O)−(CH2)−(CHOH)3−H. Its name indicates that it is a deoxy sugar, meaning that it is derived from the sugar ribose by loss of a hydroxy group. D ...

sugar molecule bound to an

adenine Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its deri ...

and to three phosphate groups. It differs from the energy-transferring molecule

adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms o ...

(ATP) by a single hydroxyl group (the -OH group on the 2'

carbon Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent—its atom making four electrons available to form covalent chemical bonds. It belongs to group 14 of the periodic table. Carbon mak ...

of the

pentose In chemistry, a pentose is a monosaccharide (simple sugar) with five carbon atoms. The chemical formula of many pentoses is , and their molecular weight is 150.13 g/mol.sugar is replaced by -H in dATP), resulting in a deoxyribose instead of a

ribose Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form composition H−(C=O)−(CHOH)4−H. The naturally-occurring form, , is a component of the ribonucleotides from which RNA is built, and so this compo ...

. Two phosphate groups can be hydrolyzed to yield deoxyadenosine monophosphate, which can then be used to synthesize DNA. Findings have also suggested that dATP can act as an energy-transferring molecule to maintain cell viability.

Synthesis

Enzymatic synthesis of deoxyadenosine triphosphate

Deoxyadenosine triphosphate is able to be enzymatically synthesized with DNA as the starting material using

deoxyribonuclease Deoxyribonuclease (DNase, for short) refers to a group of glycoprotein endonucleases which are enzymes that catalyze the hydrolytic cleavage of phosphodiester linkages in the DNA backbone, thus degrading DNA. The role of the DNase enzyme in cells ...

(DNase), nuclease P1,

adenylate kinase Adenylate kinase ( ECbr>2.7.4.3 (also known as ADK or myokinase) is a phosphotransferase enzyme that catalyzes the interconversion of the various adenosine phosphates (ATP, ADP, and AMP). By constantly monitoring phosphate nucleotide levels inside ...

, and

pyruvate kinase Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. P ...

. The synthesis starts with the heat denaturation of DNA followed by treatment with DNase I to produce oligomers. Next, the solution is treated with nuclease P1 to form deoxynucleoside monophosphates. Using a mixture of adenylate kinase and pyruvate kinase, the deoxyadenosine monophosphate was selectively converted to dATP. After purification, a purity of 90%-95% can be achieved using this method of synthesis with a 40% overall yield.

Health effects

In immunocompromised individuals

High levels of dATP in the body can be

toxic Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...

and result in impaired immune function, since dATP acts as a noncompetitive inhibitor for the DNA synthesis

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

ribonucleotide reductase. Patients with adenosine deaminase deficiency (ADA) tend to have elevated

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

dATP concentrations because

adenosine deaminase Adenosine deaminase (also known as adenosine aminohydrolase, or ADA) is an enzyme () involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues. Its primary function ...

normally curbs adenosine levels by converting it into

inosine Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring (also known as a ribofuranose) via a β-N9- glycosidic bond. It was discovered in 1965 in analysis of RNA transferase. Inosine is commonly found in tRNAs and is ...

. Deficiency of the enzyme

is known to cause immunodeficiency in individuals. Research has found that dATP may be a potential toxic metabolite in adenosine deaminase deficiency. Patients in the study who were immunodeficient and adenosine deaminase deficient were found to have over 50 times the levels of dATP in their

erythrocytes Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

compared to non-immunodeficient, adenosine deaminase deficient patients. This is abnormal and provides evidence that increased erythrocyte dATP levels are the toxic metabolites responsible for immune system deficiency in individuals with adenosine deaminase deficiency. Infusion of normal, non-enzyme deficient erythrocytes resulted in the loss of dATP in the erythrocytes of these individuals. Cells lacking the ability to

transport Transport (in British English), or transportation (in American English), is the intentional movement of humans, animals, and goods from one location to another. Modes of transport include air, land ( rail and road), water, cable, pipelin ...

phosphorylate In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...

dATP have been shown to exhibit increased resistance to the toxic effects of excessive dATP, suggesting that the toxicity of dATP is dependent on the ability to

ly phosphorylate dATP. As such, some treatments for ADA focus on reducing dATP phosphorylation by the targeted inhibition of the responsible deoxynucleoside kinases, such as

adenosine kinase Adenosine kinase (AdK; EC 2.7.1.20) is an enzyme that catalyzes the transfer of gamma-phosphate from Adenosine triphosphate ( ATP) to adenosine Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse der ...

and deoxycytidine kinase.

Deoxycytidine Deoxycytidine is a deoxyribonucleoside, a component of deoxyribonucleic acid. It is similar to the ribonucleoside cytidine, but with one hydroxyl group removed from the C2' position. Deoxycytidine can be phosphorylated at C5' of the deoxyribos ...

administered

intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

has also been used as an ADA treatment, although a clinical study found that deoxycytidine had only limited clinical effects on the T-cell immunity of ADA patients without discounting that some patients may respond more significantly to deoxycytidine therapy. In cardiac muscle In

cardiac The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...

myosin, dATP has been shown to be a viable alternative to ATP as an energy substrate for facilitating cross-bridge formation. In an experiment involving canine

dilated cardiomyopathy Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. Co ...

(DCM), increasing cardiac dATP was found to be a potentially effective treatment for DCM. dATP can increase contractility as well as systolic pressure in a failing heart and that it can also enhance contraction as well as restoring the cardiac pump function. Further, dATP has been found not only to restore normal systolic function in patients with cardiovascular impairments but that it can also increase contraction, as well as the rate of cross-bridge of the cardiac muscle of patients in their end-stage congestive heart failure without hindering, or impairing the systolic relaxation.

dATP inhibition of Ribonucleotide reductases

The class Ia Ribonucleotide reductase of the '' E.coli'' confirms that dATP regulates the activities of the Ribonucleotide reductase by binding to the A site of the nucleotide binding sites. The inhibition of the class Ia Ribonucleotide reductase of the E. coli by the dATP is due to the increased space between the cysteine and

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the G ...

radical cofactor in C-site and 𝛃2 respectively, which in turn inhibits the formation of the active site which is usually necessary reduction. In human Ribonucleotide reductase, dATP induced α6 structure inhibits the activity of the Ribonucleotide reductase by preventing 𝛃 subunit from accessing the active site of the of 𝛂 subunit.

References

External links

KEGG KEGG (Kyoto Encyclopedia of Genes and Genomes) is a collection of databases dealing with genomes, biological pathways, diseases, drugs, and chemical substances. KEGG is utilized for bioinformatics research and education, including data analysis i ...

entry o
dATP
{{Purinergics Nucleotides Phosphate esters