Nucleoside triphosphate

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A nucleoside triphosphate is a nucleoside containing a nitrogenous base bound to a 5-carbon sugar (either ribose or deoxyribose), with three phosphate groups bound to the sugar. [1] They are the molecular precursors of both DNA and RNA, which are chains of nucleotides made through the processes of DNA replication and transcription. [2] Nucleoside triphosphates also serve as a source of energy for cellular reactions [3] and are involved in signalling pathways. [4]

Contents

Nucleoside triphosphates cannot be absorbed well, so they are typically synthesized within the cell. [5] Synthesis pathways differ depending on the specific nucleoside triphosphate being made, but given the many important roles of nucleoside triphosphates, synthesis is tightly regulated in all cases. [6] Nucleoside analogues may also be used to treat viral infections. [7] For example, azidothymidine (AZT) is a nucleoside analogue used to prevent and treat HIV/AIDS. [8]

Naming

The term nucleoside refers to a nitrogenous base linked to a 5-carbon sugar (either ribose or deoxyribose). [1] Nucleotides are nucleosides covalently linked to one or more phosphate groups. [9] To provide information about the number of phosphates, nucleotides may instead be referred to as nucleoside (mono, di, or tri) phosphates. [10] Thus, nucleoside triphosphates are a type of nucleotide. [10]

Nucleotides are commonly abbreviated with 3 letters (4 or 5 in case of deoxy- or dideoxy-nucleotides). The first letter indicates the identity of the nitrogenous base (e.g., A for adenine, G for guanine), the second letter indicates the number of phosphates (mono, di, tri), and the third letter is P, standing for phosphate. [11] Nucleoside triphosphates that contain ribose as the sugar are conventionally abbreviated as NTPs, while nucleoside triphosphates containing deoxyribose as the sugar are abbreviated as dNTPs. For example, dATP stands for deoxyribose adenosine triphosphate. NTPs are the building blocks of RNA, and dNTPs are the building blocks of DNA. [12]

The carbons of the sugar in a nucleoside triphosphate are numbered around the carbon ring starting from the original carbonyl of the sugar. Conventionally, the carbon numbers in a sugar are followed by the prime symbol (‘) to distinguish them from the carbons of the nitrogenous base. The nitrogenous base is linked to the 1’ carbon through a glycosidic bond, and the phosphate groups are covalently linked to the 5’ carbon. [13] The first phosphate group linked to the sugar is termed the α-phosphate, the second is the β-phosphate, and the third is the γ-phosphate; these are linked to one another by two phosphoanhydride bonds. [14]

Schematic showing the structure of nucleoside triphosphates. Nucleosides consist of a 5-carbon sugar (pentose) connected to a nitrogenous base through a 1' glycosidic bond. Nucleotides are nucleosides with a variable number of phosphate groups connected to the 5' carbon. Nucleoside triphosphates are a specific type of nucleotide. This figure also shows the five common nitrogenous bases found in DNA and RNA on the right. Nucleotides 1.svg
Schematic showing the structure of nucleoside triphosphates. Nucleosides consist of a 5-carbon sugar (pentose) connected to a nitrogenous base through a 1' glycosidic bond. Nucleotides are nucleosides with a variable number of phosphate groups connected to the 5' carbon. Nucleoside triphosphates are a specific type of nucleotide. This figure also shows the five common nitrogenous bases found in DNA and RNA on the right.

DNA and RNA synthesis

In nucleic acid synthesis, the 3' OH of a growing chain of nucleotides attacks the a-phosphate on the next NTP to be incorporated (blue), resulting in a phosphodiester linkage and the release of pyrophosphate (PPi). This figure shows DNA synthesis, but RNA synthesis occurs through the same mechanism. DNA synthesis EN.png
In nucleic acid synthesis, the 3’ OH of a growing chain of nucleotides attacks the α-phosphate on the next NTP to be incorporated (blue), resulting in a phosphodiester linkage and the release of pyrophosphate (PPi). This figure shows DNA synthesis, but RNA synthesis occurs through the same mechanism.

The cellular processes of DNA replication and transcription involve DNA and RNA synthesis, respectively. DNA synthesis uses dNTPs as substrates, while RNA synthesis uses rNTPs as substrates. [2] NTPs cannot be converted directly to dNTPs. DNA contains four different nitrogenous bases: adenine, guanine, cytosine and thymine. RNA also contains adenine, guanine, and cytosine, but replaces thymine with uracil. [15] Thus, DNA synthesis requires dATP, dGTP, dCTP, and dTTP as substrates, while RNA synthesis requires ATP, GTP, CTP, and UTP.

Nucleic acid synthesis is catalyzed by either DNA polymerase or RNA polymerase for DNA and RNA synthesis respectively. [16] These enzymes covalently link the free -OH group on the 3’ carbon of a growing chain of nucleotides to the α-phosphate on the 5’ carbon of the next (d)NTP, releasing the β- and γ-phosphate groups as pyrophosphate (PPi). [17] This results in a phosphodiester linkage between the two (d)NTPs. The release of PPi provides the energy necessary for the reaction to occur. [17] It is important to note that nucleic acid synthesis occurs exclusively in the 5’ to 3’ direction.

Nucleoside triphosphate metabolism

Given their importance in the cell, the synthesis and degradation of nucleoside triphosphates is under tight control. [6] This section focuses on nucleoside triphosphate metabolism in humans, but the process is fairly conserved among species. [18] Nucleoside triphosphates cannot be absorbed well, so all nucleoside triphosphates are typically made de novo . [19] The synthesis of ATP and GTP (purines) differs from the synthesis of CTP, TTP, and UTP (pyrimidines). Both purine and pyrimidine synthesis use phosphoribosyl pyrophosphate (PRPP) as a starting molecule. [20]

The conversion of NTPs to dNTPs can only be done in the diphosphate form. Typically a NTP has one phosphate removed to become a NDP, then is converted to a dNDP by an enzyme called ribonucleotide reductase, then a phosphate is added back to give a dNTP. [21]

Purine synthesis

A nitrogenous base called hypoxanthine is assembled directly onto PRPP. [22] This results in a nucleotide called inosine monophosphate (IMP). IMP is then converted to either a precursor to AMP or GMP. Once AMP or GMP are formed, they can be phosphorylated by ATP to their diphosphate and triphosphate forms. [23]

Purine synthesis is regulated by the allosteric inhibition of IMP formation by the adenine or guanine nucleotides. [24] AMP and GMP also competitively inhibit the formation of their precursors from IMP. [25]

Pyrimidine synthesis

A nitrogenous base called orotate is synthesized independently of PRPP. [25] After orotate is made it is covalently attached to PRPP. This results in a nucleotide called orotate monophosphate (OMP). [26] OMP is converted to UMP, which can then be phosphorylated by ATP to UDP and UTP. UTP can then be converted to CTP by a deamination reaction. [27] TTP is not a substrate for nucleic acid synthesis, so it is not synthesized in the cell. Instead, dTTP is made indirectly from either dUDP or dCDP after conversion to their respective deoxyribose forms. [20]

Pyrimidine synthesis is regulated by the allosteric inhibition of orotate synthesis by UDP and UTP. PRPP and ATP are also allosteric activators of orotate synthesis. [28]

Ribonucleotide reductase

Ribonucleotide reductase (RNR) is the enzyme responsible for converting NTPs to dNTPs. Given that dNTPs are used in DNA replication, the activity of RNR is tightly regulated. [6] It is important to note that RNR can only process NDPs, so NTPs are first dephosphorylated to NDPs before conversion to dNDPs. [29] dNDPs are then typically re-phosphorylated. RNR has 2 subunits and 3 sites: the catalytic site, activity (A) site, and specificity (S) site. [29] The catalytic site is where the NDP to dNDP reaction takes place, the activity site determines whether or not the enzyme is active, and the specificity site determines which reaction takes place in the catalytic site.

The activity site can bind either ATP or dATP. [30] When bound to ATP, RNR is active. When ATP or dATP is bound to the S site, RNR will catalyze synthesis of dCDP and dUDP from CDP and UDP. dCDP and dUDP can go on to indirectly make dTTP. dTTP bound to the S site will catalyze synthesis of dGDP from GDP, and binding of dGDP to the S site will promote synthesis of dADP from ADP. [31] dADP is then phosphorylated to give dATP, which can bind to the A site and turn RNR off. [30]

Other cellular roles

ATP as a source of cellular energy

The energy released during hydrolysis of adenosine tripshophate (ATP), shown here, is frequently coupled with energetically unfavourable cellular reactions. Adenosintriphosphat protoniert.svg
The energy released during hydrolysis of adenosine tripshophate (ATP), shown here, is frequently coupled with energetically unfavourable cellular reactions.

ATP is the primary energy currency of the cell. [32] Despite being synthesized through the metabolic pathway described above, it is primarily synthesized during both cellular respiration [33] and photosynthesis [34] by ATP synthase. ATP synthase couples the synthesis of ATP from ADP and phosphate with an electrochemical gradient generated by the pumping of protons through either the inner mitochondrial membrane (cellular respiration) or the thylakoid membrane (photosynthesis). [35] This electrochemical gradient is necessary because the formation of ATP is energetically unfavourable.

The hydrolysis of ATP to ADP and Pi proceeds as follows: [36]

This reaction is energetically favourable and releases 30.5 kJ/mol of energy. [3] In the cell, this reaction is often coupled with unfavourable reactions to provide the energy for them to proceed. [37] GTP is occasionally used for energy-coupling in a similar manner. [38]

Binding of a ligand to a G protein-coupled receptor allows GTP to bind the G protein. This causes the alpha subunit to leave and act as a downstream effector. Activatoin-Adenylate cyclase-outlined.svg
Binding of a ligand to a G protein-coupled receptor allows GTP to bind the G protein. This causes the alpha subunit to leave and act as a downstream effector.

GTP signal transduction

GTP is essential for signal transduction, especially with G proteins. G proteins are coupled with a cell membrane bound receptor. [4] This whole complex is called a G protein-coupled receptor (GPCR). G proteins can bind either GDP or GTP. When bound to GDP, G proteins are inactive. When a ligand binds a GPCR, an allosteric change in the G protein is triggered, causing GDP to leave and be replaced by GTP. [39] GTP activates the alpha subunit of the G protein, causing it to dissociate from the G protein and act as a downstream effector. [39]

Nucleoside analogues

Nucleoside analogues can be used to treat viral infections. [40] Nucleoside analogues are nucleosides that are structurally similar (analogous) to the nucleosides used in DNA and RNA synthesis. [41] Once these nucleoside analogues enter a cell, they can become phosphorylated by a viral enzyme. The resulting nucleotides are similar enough to the nucleotides used in DNA or RNA synthesis to be incorporated into growing DNA or RNA strands, but they do not have an available 3' OH group to attach the next nucleotide, causing chain termination. [42] This can be exploited for therapeutic uses in viral infections because viral DNA polymerase recognizes certain nucleotide analogues more readily than eukaryotic DNA polymerase. [40] For example, azidothymidine is used in the treatment of HIV/AIDS. [8] Some less selective nucleoside analogues can be used as chemotherapy agents to treat cancer, [43] such as cytosine arabinose (ara-C) in the treatment of certain forms of leukemia. [7]

Resistance to nucleoside analogues is common, and is frequently due to a mutation in the enzyme that phosphorylates the nucleoside after entry into the cell. [7] This is common in nucleoside analogues used to treat HIV/AIDS. [44]

See also

Related Research Articles

<span class="mw-page-title-main">Nucleotide</span> Biological molecules constituting nucleic acids

Nucleotides are organic molecules composed of a nitrogenous base, a pentose sugar 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 biomolecules within all life-forms on Earth. Nucleotides are obtained in the diet and are also synthesized from common nutrients by the liver.

<span class="mw-page-title-main">Nucleobase</span> Nitrogen-containing biological compounds that form nucleosides

Nucleobases are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basic building blocks of nucleic acids. The ability of nucleobases to form base pairs and to stack one upon another leads directly to long-chain helical structures such as ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Five nucleobases—adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U)—are called primary or canonical. They function as the fundamental units of the genetic code, with the bases A, G, C, and T being found in DNA while A, G, C, and U are found in RNA. Thymine and uracil are distinguished by merely the presence or absence of a methyl group on the fifth carbon (C5) of these heterocyclic six-membered rings. In addition, some viruses have aminoadenine (Z) instead of adenine. It differs in having an extra amine group, creating a more stable bond to thymine.

<span class="mw-page-title-main">Nucleoside</span> Any of several glycosylamines comprising a nucleobase and a sugar molecule

Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase and a five-carbon sugar whereas a nucleotide is composed of a nucleobase, a five-carbon sugar, and one or more phosphate groups. In a nucleoside, the anomeric carbon is linked through a glycosidic bond to the N9 of a purine or the N1 of a pyrimidine. Nucleotides are the molecular building blocks of DNA and RNA.

<span class="mw-page-title-main">Guanosine triphosphate</span> Chemical compound

Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only difference being that nucleotides like GTP have phosphates on their ribose sugar. GTP has the guanine nucleobase attached to the 1' carbon of the ribose and it has the triphosphate moiety attached to ribose's 5' carbon.

<span class="mw-page-title-main">Ribonucleotide</span> Nucleotide containing ribose as its pentose component

In biochemistry, a ribonucleotide is a nucleotide containing ribose as its pentose component. It is considered a molecular precursor of nucleic acids. Nucleotides are the basic building blocks of DNA and RNA. Ribonucleotides themselves are basic monomeric building blocks for RNA. Deoxyribonucleotides, formed by reducing ribonucleotides with the enzyme ribonucleotide reductase (RNR), are essential building blocks for DNA. There are several differences between DNA deoxyribonucleotides and RNA ribonucleotides. Successive nucleotides are linked together via phosphodiester bonds.

<span class="mw-page-title-main">Ribonucleotide reductase</span> Class of enzymes

Ribonucleotide reductase (RNR), also known as ribonucleoside diphosphate reductase (rNDP), is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. It catalyzes this formation by removing the 2'-hydroxyl group of the ribose ring of nucleoside diphosphates. This reduction produces deoxyribonucleotides. Deoxyribonucleotides in turn are used in the synthesis of DNA. The reaction catalyzed by RNR is strictly conserved in all living organisms. Furthermore, RNR plays a critical role in regulating the total rate of DNA synthesis so that DNA to cell mass is maintained at a constant ratio during cell division and DNA repair. A somewhat unusual feature of the RNR enzyme is that it catalyzes a reaction that proceeds via a free radical mechanism of action. The substrates for RNR are ADP, GDP, CDP and UDP. dTDP is synthesized by another enzyme from dTMP.

In molecular biology, biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. This process often consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides. Biosynthesis is usually synonymous with anabolism.

<span class="mw-page-title-main">Inosinic acid</span> Chemical compound

Inosinic acid or inosine monophosphate (IMP) is a nucleotide. Widely used as a flavor enhancer, it is typically obtained from chicken byproducts or other meat industry waste. Inosinic acid is important in metabolism. It is the ribonucleotide of hypoxanthine and the first nucleotide formed during the synthesis of purine nucleotides. It can also be formed by the deamination of adenosine monophosphate by AMP deaminase. It can be hydrolysed to inosine.

<span class="mw-page-title-main">Nucleoside-diphosphate kinase</span> Class of enzymes

Nucleoside-diphosphate kinases are enzymes that catalyze the exchange of terminal phosphate between different nucleoside diphosphates (NDP) and triphosphates (NTP) in a reversible manner to produce nucleotide triphosphates. Many NDP serve as acceptor while NTP are donors of phosphate group. The general reaction via ping-pong mechanism is as follows: XDP + YTP ←→ XTP + YDP. NDPK activities maintain an equilibrium between the concentrations of different nucleoside triphosphates such as, for example, when guanosine triphosphate (GTP) produced in the citric acid (Krebs) cycle is converted to adenosine triphosphate (ATP). Other activities include cell proliferation, differentiation and development, signal transduction, G protein-coupled receptor, endocytosis, and gene expression.

<span class="mw-page-title-main">Succinyl coenzyme A synthetase</span> Class of enzymes

Succinyl coenzyme A synthetase is an enzyme that catalyzes the reversible reaction of succinyl-CoA to succinate. The enzyme facilitates the coupling of this reaction to the formation of a nucleoside triphosphate molecule from an inorganic phosphate molecule and a nucleoside diphosphate molecule. It plays a key role as one of the catalysts involved in the citric acid cycle, a central pathway in cellular metabolism, and it is located within the mitochondrial matrix of a cell.

<span class="mw-page-title-main">Purine nucleoside phosphorylase</span> Enzyme

Purine nucleoside phosphorylase, PNP, PNPase or inosine phosphorylase is an enzyme that in humans is encoded by the NP gene. It catalyzes the chemical reaction

<span class="mw-page-title-main">Nucleic acid metabolism</span> Process

Nucleic acid metabolism is a collective term that refers to the variety of chemical reactions by which nucleic acids are either synthesized or degraded. Nucleic acids are polymers made up of a variety of monomers called nucleotides. Nucleotide synthesis is an anabolic mechanism generally involving the chemical reaction of phosphate, pentose sugar, and a nitrogenous base. Degradation of nucleic acids is a catabolic reaction and the resulting parts of the nucleotides or nucleobases can be salvaged to recreate new nucleotides. Both synthesis and degradation reactions require multiple enzymes to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.

A ribonucleotide tri-phosphate (rNTP) is composed of a ribose sugar, 3 phosphate groups attached via diester bonds to the 5' oxygen on the ribose and a nitrogenous base attached to the 1' carbon on the ribose. rNTP's are also referred to as NTPs while the deoxyribose version is referred to as dNTPs. The nitrogenous base can either be a purine such as a Adenine or Guanine or a pyrimidine such as a Uracil or Cytosine. rNTPs have significant biological uses, they can serve as building blocks of RNA synthesis, primers in DNA replication, stores of chemical energy, chiefly Adenosine triphosphate (ATP) and more.

Pyrimidine biosynthesis occurs both in the body and through organic synthesis.

<span class="mw-page-title-main">Ribose 5-phosphate</span> Chemical compound

Ribose 5-phosphate (R5P) is both a product and an intermediate of the pentose phosphate pathway. The last step of the oxidative reactions in the pentose phosphate pathway is the production of ribulose 5-phosphate. Depending on the body's state, ribulose 5-phosphate can reversibly isomerize to ribose 5-phosphate. Ribulose 5-phosphate can alternatively undergo a series of isomerizations as well as transaldolations and transketolations that result in the production of other pentose phosphates as well as fructose 6-phosphate and glyceraldehyde 3-phosphate.

Phosphoribosylformylglycinamidine cyclo-ligase is the fifth enzyme in the de novo synthesis of purine nucleotides. It catalyzes the reaction to form 5-aminoimidazole ribotide (AIR) from formylglycinamidine-ribonucleotide FGAM. This reaction closes the ring and produces a 5-membered imidazole ring of the purine nucleus (AIR):

Purine metabolism refers to the metabolic pathways to synthesize and break down purines that are present in many organisms.

<span class="mw-page-title-main">Deoxycytidine kinase</span> Protein-coding gene in the species Homo sapiens

Deoxycytidine kinase (dCK) is an enzyme which is encoded by the DCK gene in humans. dCK predominantly phosphorylates deoxycytidine (dC) and converts dC into deoxycytidine monophosphate. dCK catalyzes one of the initial steps in the nucleoside salvage pathway and has the potential to phosphorylate other preformed nucleosides, specifically deoxyadenosine (dA) and deoxyguanosine (dG), and convert them into their monophosphate forms. There has been recent biomedical research interest in investigating dCK's potential as a therapeutic target for different types of cancer.

<span class="mw-page-title-main">Ribose-phosphate diphosphokinase</span> Class of enzymes

Ribose-phosphate diphosphokinase is an enzyme that converts ribose 5-phosphate into phosphoribosyl pyrophosphate (PRPP). It is classified under EC 2.7.6.1.

<span class="mw-page-title-main">NDPCP</span> Nucleotide

5'-guanosyl-methylene-triphosphate (GDPCP) and 5'-adenosyl-methylene-triphosphate (ADPCP) are analogues of guanosine 5'-triphosphate (GTP) and adenosine 5'-triphosphate (ATP), which store chemical energy from metabolism in the cell. Hydrolysis of nucleoside triphosphates (NTPs) such as ATP and GTP yields energy, inorganic phosphate, and either NDP or NMP. GDPCP and ADPCP are not subject to hydrolysis under the same conditions as NTPs; it is this property which makes them useful in experiments in biochemistry and molecular biology.

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