Nucleoside triphosphate
A nucleoside triphosphate is a
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
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]
DNA and RNA synthesis
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
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
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 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]
GTP signal transduction
GTP is essential for
Nucleoside analogues
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
References
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