Editing Nucleoside triphosphate (section)

== Nucleoside triphosphate metabolism ==
Given their importance in the cell, the synthesis and degradation of nucleoside triphosphates is under tight control.<ref name="Wyngaarden_1976" /> This section focuses on nucleoside triphosphate metabolism in humans, but the process is fairly conserved among species.<ref>{{cite journal | vauthors = Samant S, Lee H, Ghassemi M, Chen J, Cook JL, Mankin AS, Neyfakh AA | title = Nucleotide biosynthesis is critical for growth of bacteria in human blood | journal = PLOS Pathogens | volume = 4 | issue = 2 | pages = e37 | date = February 2008 | pmid = 18282099 | doi = 10.1371/journal.ppat.0040037 | pmc=2242838 | doi-access = free }}</ref> Nucleoside triphosphates cannot be absorbed well, so all nucleoside triphosphates are typically made ''[[De novo synthesis|de novo]]''.<ref>{{cite book | vauthors = Berg JM, Tymoczko JL, Stryer L |date=2002|title=Nucleotide Biosynthesis|url=https://www.ncbi.nlm.nih.gov/books/NBK21216/}}</ref> The synthesis of ATP and GTP ([[purine]]s) differs from the synthesis of CTP, TTP, and UTP ([[pyrimidine]]s). Both purine and pyrimidine synthesis use [[phosphoribosyl pyrophosphate]] (PRPP) as a starting molecule.<ref name=":5">{{cite web | url = https://themedicalbiochemistrypage.org/nucleotide-metabolism.php|title=Nucleotide Metabolism: Nucleic Acid Synthesis|website=themedicalbiochemistrypage.org|access-date=2017-11-15}}</ref>

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.<ref name="Stubbe_1990">{{cite journal | vauthors = Stubbe J | title = Ribonucleotide reductases: amazing and confusing | journal = The Journal of Biological Chemistry | volume = 265 | issue = 10 | pages = 5329–32 | year = 1990 | doi = 10.1016/S0021-9258(19)39357-3 | pmid = 2180924 | url = http://www.jbc.org/content/265/10/5329.full.pdf | doi-access = free }}</ref>

=== Purine synthesis ===
A nitrogenous base called [[hypoxanthine]] is assembled directly onto PRPP.<ref>{{cite book| vauthors = Berg J, Tymoczko JL, Stryer L |date=2002 |title=Purine Bases Can Be Synthesized de Novo or Recycled by Salvage Pathways|url=https://www.ncbi.nlm.nih.gov/books/NBK22385/}}</ref> 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.<ref>{{Cite news|url=http://www.biochemden.com/purine-synthesis/|title=Purine Synthesis : Synthesis of Purine RiboNucleotides|date=2016-03-16|work=BiochemDen.com|access-date= 15 November 2017 }}</ref>

Purine synthesis is regulated by the [[Allosteric regulation|allosteric inhibition]] of IMP formation by the adenine or guanine nucleotides.<ref>{{cite book | vauthors = Berg JM, Tymoczko JL, Stryer L |date=2002|title=Key Steps in Nucleotide Biosynthesis Are Regulated by Feedback Inhibition|url=https://www.ncbi.nlm.nih.gov/books/NBK22428/}}</ref> AMP and GMP also [[Competitive inhibition|competitively inhibit]] the formation of their precursors from IMP.<ref name="Nierlich_1965">{{cite journal | vauthors = Nierlich DP, Magasanik B | title = Regulation of purine ribonucleotide synthesis by end product inhibition. the effect of adenine and guanine ribonucleotides on the 5'-phosphoribosyl-pyrophosphate amidotransferase of aerobacter aerogenes | journal = The Journal of Biological Chemistry | volume = 240 | pages = 358–65 | year = 1965 | doi = 10.1016/S0021-9258(18)97657-X | pmid = 14253438 | doi-access = free }}</ref>

=== Pyrimidine synthesis ===
A nitrogenous base called [[orotate]] is synthesized independently of PRPP.<ref name="Nierlich_1965" /> After orotate is made it is covalently attached to PRPP. This results in a nucleotide called orotate monophosphate (OMP).<ref>{{cite journal | vauthors = Moffatt BA, Ashihara H | title = Purine and pyrimidine nucleotide synthesis and metabolism | journal = The Arabidopsis Book | volume = 1 | pages = e0018 | date = April 2002 | pmid = 22303196 | pmc = 3243375 | doi = 10.1199/tab.0018 }}</ref> 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.<ref>{{cite web|url=https://www.cliffsnotes.com/study-guides/biology/biochemistry-ii/purines-and-pyrimidines/pyrimidine-metabolism|title=Pyrimidine Metabolism|website=www.cliffsnotes.com|access-date=2017-11-15}}</ref> 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.<ref name=":5" />

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.<ref>{{cite journal | vauthors = Lane AN, Fan TW | title = Regulation of mammalian nucleotide metabolism and biosynthesis | journal = Nucleic Acids Research | volume = 43 | issue = 4 | pages = 2466–85 | date = February 2015 | pmid = 25628363 | doi = 10.1093/nar/gkv047 | pmc=4344498}}</ref>

=== 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.<ref name="Wyngaarden_1976"/> RNR can only process NDPs, so NTPs are first dephosphorylated to NDPs before conversion to dNDPs.<ref name="auto">{{cite journal | vauthors = Kolberg M, Strand KR, Graff P, Andersson KK | title = Structure, function, and mechanism of ribonucleotide reductases | journal = Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics | volume = 1699 | issue = 1–2 | pages = 1–34 | date = June 2004 | pmid = 15158709 | doi = 10.1016/j.bbapap.2004.02.007 }}</ref> dNDPs are then typically re-phosphorylated. RNR has 2 subunits and 3 sites: the catalytic site, activity (A) site, and specificity (S) site.<ref name="auto"/> 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.<ref name=":7">{{cite book |doi=10.1016/B978-0-12-386931-9.00014-3 |chapter=The Structural Basis for the Allosteric Regulation of Ribonucleotide Reductase |title=Oligomerization in Health and Disease |series=Progress in Molecular Biology and Translational Science |year=2013 | vauthors = Ahmad MF, Dealwis CG |volume=117 |pages=389–410 |pmid=23663976 |pmc=4059395 |isbn=9780123869319 }}</ref> 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.<ref>{{cite journal | vauthors = Fairman JW, Wijerathna SR, Ahmad MF, Xu H, Nakano R, Jha S, Prendergast J, Welin RM, Flodin S, Roos A, Nordlund P, Li Z, Walz T, Dealwis CG | title = Structural basis for allosteric regulation of human ribonucleotide reductase by nucleotide-induced oligomerization | journal = Nature Structural & Molecular Biology | volume = 18 | issue = 3 | pages = 316–22 | date = March 2011 | pmid = 21336276 | doi = 10.1038/nsmb.2007 | pmc=3101628}}</ref> dADP is then phosphorylated to give dATP, which can bind to the A site and turn RNR off.<ref name=":7" />