Page last updated: 2024-10-24

nucleoside triphosphate biosynthetic process

Definition

Target type: biologicalprocess

The chemical reactions and pathways resulting in the formation of a nucleoside triphosphate, a compound consisting of a nucleobase linked to a deoxyribose or ribose sugar esterified with triphosphate on the sugar. [GOC:go_curators, ISBN:0198506732]

Nucleoside triphosphate biosynthesis is a fundamental process in all living organisms, responsible for generating the building blocks of DNA and RNA. These building blocks, known as nucleoside triphosphates (NTPs), are composed of a nitrogenous base (adenine, guanine, cytosine, thymine, or uracil), a five-carbon sugar (ribose or deoxyribose), and three phosphate groups. The process involves multiple enzymatic steps and can be broadly divided into two main pathways: de novo synthesis and salvage pathways.

**De novo synthesis:**

* **Purine biosynthesis:** Initiates with the formation of PRPP (phosphoribosyl pyrophosphate) from ribose-5-phosphate, followed by a series of complex reactions involving amino acids (glycine, glutamine, aspartate), tetrahydrofolate, and various enzymes like amidophosphoribosyltransferase, glycinamide ribotide synthetase, GAR transformylase, and others. The pathway culminates in the synthesis of IMP (inosine monophosphate), a precursor for both AMP (adenosine monophosphate) and GMP (guanosine monophosphate).
* **Pyrimidine biosynthesis:** Begins with the condensation of carbamoyl phosphate and aspartate to form carbamoyl aspartate. Subsequent steps involve reactions catalyzed by dihydroorotase, dihydroorotate dehydrogenase, and orotate phosphoribosyltransferase, leading to the formation of UMP (uridine monophosphate). UMP is then converted to CTP (cytidine triphosphate) via a series of enzymatic reactions.

**Salvage pathways:**

* These pathways utilize pre-existing purine and pyrimidine bases or nucleosides obtained from the breakdown of nucleic acids or dietary sources.
* The major enzymes involved in salvage pathways are adenine phosphoribosyltransferase (APRT) for adenine, hypoxanthine-guanine phosphoribosyltransferase (HGPRT) for hypoxanthine and guanine, and thymidine kinase for thymidine.

**Phosphorylation of nucleoside monophosphates:**

* Once nucleoside monophosphates (AMP, GMP, CMP, UMP) are formed, they are sequentially phosphorylated to diphosphates and then triphosphates by specific kinases. These reactions require ATP as the phosphate donor.

**Regulation:**

* Nucleoside triphosphate biosynthesis is tightly regulated to maintain balanced levels of NTPs. This regulation involves feedback inhibition, substrate availability, and allosteric regulation of key enzymes.

**Clinical significance:**

* Defects in nucleoside triphosphate biosynthesis can lead to various genetic disorders, including Lesch-Nyhan syndrome (deficiency in HGPRT), SCID (severe combined immunodeficiency) due to defects in purine biosynthesis, and orotic aciduria (deficiency in uridine monophosphate synthase).
* Some anticancer drugs target specific enzymes involved in NTP synthesis, inhibiting cell proliferation.

This complex and vital process ensures the constant supply of building blocks for DNA and RNA, crucial for genetic information storage, gene expression, and overall cell function.'
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Proteins (2)

ProteinDefinitionTaxonomy
Nucleoside diphosphate kinase BA nucleoside diphosphate kinase B that is encoded in the genome of human. [PRO:DAN, UniProtKB:P22392]Homo sapiens (human)
Adenylate kinase isoenzyme 1An adenylate kinase isoenzyme 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P00568]Homo sapiens (human)

Compounds (21)

CompoundDefinitionClassesRoles
adenosine monophosphateAdenosine Monophosphate: Adenine nucleotide containing one phosphate group esterified to the sugar moiety in the 2'-, 3'-, or 5'-position.adenosine 5'-phosphate;
purine ribonucleoside 5'-monophosphate
adenosine A1 receptor agonist;
cofactor;
EC 3.1.3.1 (alkaline phosphatase) inhibitor;
EC 3.1.3.11 (fructose-bisphosphatase) inhibitor;
fundamental metabolite;
micronutrient;
nutraceutical
2'-deoxy-5'-adenosine monophosphate2'-deoxy-5'-adenosine monophosphate: RN given refers to parent cpd

2'-deoxyadenosine 5'-monophosphate : A purine 2'-deoxyribonucleoside 5'-monophosphate having adenine as the nucleobase.
2'-deoxyadenosine 5'-phosphate;
purine 2'-deoxyribonucleoside 5'-monophosphate
fundamental metabolite
adefoviradefovir : A member of the class of phosphonic acids that is methylphosphonic acid in which one of the methyl hydrogens has been replaced by a 2-(6-amino-9H-purin-9-yl)ethoxy group. An inhibitor of HIV-1 reverse transcriptase, the bis(t-butoxycarbonyloxymethyl) ester (dipivoxil ester) prodrug is used to treat chronic hepatitis B viral infection.

adefovir: inhibitor of African swine fever virus

adefovir(1-) : A organophosphonate oxoanion obtained by removal of a proton from the phosphonate group of adefovir, a nucleoside reverse transcriptase inhibitor. It is the major microspecies at pH 7.3 (according to Marvin v 6.2.0.).
6-aminopurines;
ether;
phosphonic acids
antiviral drug;
DNA synthesis inhibitor;
drug metabolite;
HIV-1 reverse transcriptase inhibitor;
nephrotoxic agent
thymidine 5'-diphosphatedTDP : A thymidine phosphate having a diphosphate group at the 5'-position.

thymidine 5'-diphosphate: see also record for thymidine 3',5'-diphosphate, RN 2863-04-9
pyrimidine 2'-deoxyribonucleoside 5'-diphosphate;
thymidine phosphate
Escherichia coli metabolite;
mouse metabolite
tenofovirtenofovir (anhydrous) : A member of the class of phosphonic acids that is methylphosphonic acid in which one of the methyl hydrogens is replaced by a [(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy group. An inhibitor of HIV-1 reverse transcriptase, the bis(isopropyloxycarbonyloxymethyl) ester (disoproxil ester) prodrug is used as the fumaric acid salt in combination therapy for the treatment of HIV infection.nucleoside analogue;
phosphonic acids
antiviral drug;
drug metabolite;
HIV-1 reverse transcriptase inhibitor
alvocidibalvocidib : A synthetic dihydroxyflavone that is 5,7-dihydroxyflavone which is substituted by a 3-hydroxy-1-methylpiperidin-4-yl group at position 8 and by a chlorine at the 2' position (the (-)-3S,4R stereoisomer). A cyclin-dependent kinase 9 (CDK9) inhibitor, it has been studied for the treatment of acute myeloid leukaemia, arthritis and atherosclerotic plaque formation.

alvocidib: structure given in first source
dihydroxyflavone;
hydroxypiperidine;
monochlorobenzenes;
tertiary amino compound
antineoplastic agent;
antirheumatic drug;
apoptosis inducer;
EC 2.7.11.22 (cyclin-dependent kinase) inhibitor
saracatinibaromatic ether;
benzodioxoles;
diether;
N-methylpiperazine;
organochlorine compound;
oxanes;
quinazolines;
secondary amino compound
anticoronaviral agent;
antineoplastic agent;
apoptosis inducer;
autophagy inducer;
EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor;
radiosensitizing agent
vx 702VX 702: a p38 MAP kinase inhibitorphenylpyridine
chir-265aromatic ether
pf-562,271indoles
buparlisibNVP-BKM120: a pan class I PI3 kinase inhibitor with antineoplastic activity; structure in first sourceaminopyridine;
aminopyrimidine;
morpholines;
organofluorine compound
antineoplastic agent;
EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor
pha 848125N,1,4,4-tetramethyl-8-((4-(4-methylpiperazin-1-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo(4,3-h)quinazoline-3-carboxamide: a cyclin dependent kinase inhibitor
gdc 0941pictrelisib : A sulfonamide composed of indazole, morpholine, and methylsulfonyl-substituted piperazine rings bound to a thienopyrimidine ring.indazoles;
morpholines;
piperazines;
sulfonamide;
thienopyrimidine
EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor
cudc 1017-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide: a histone deacetylase inhibitor; structure in first source
mln 8237MLN 8237: an aurora kinase A inhibitorbenzazepine
pci 32765ibrutinib : A member of the class of acrylamides that is (3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine in which the piperidine nitrogen is replaced by an acryloyl group. A selective and covalent inhibitor of the enzyme Bruton's tyrosine kinase, it is used for treatment of B-cell malignancies.

ibrutinib: a Btk protein inhibitor
acrylamides;
aromatic amine;
aromatic ether;
N-acylpiperidine;
pyrazolopyrimidine;
tertiary carboxamide
antineoplastic agent;
EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor
tak 733
entrectinibentrectinib : A member of the class of indazoles that is 1H-indazole substituted by [4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzoyl]amino and 3,5-difluorobenzyl groups at positions 3 and 5, respectively. It is a potent inhibitor of TRKA, TRKB, TRKC, ROS1, and ALK (IC50 values of 0.1 to 1.7 nM), and used for the treatment of NTRK, ROS1 and ALK gene fusion-positive solid tumours.

entrectinib: inhibits TRK, ROS1, and ALK receptor tyrosine kinases; structure in first source
benzamides;
difluorobenzene;
indazoles;
N-methylpiperazine;
oxanes;
secondary amino compound;
secondary carboxamide
antibacterial agent;
antineoplastic agent;
apoptosis inducer;
EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor
gsk 2126458omipalisib : A member of the class of quinolines that is quinoline which is substituted by pyridazin-4-yl and 5-[(2,4-difluorobenzene-1-sulfonyl)amino]-6-methoxypyridin-3-yl groups at positions 4 and 6, respectively. It is a highly potent inhibitor of PI3K and mTOR developed by GlaxoSmithKline and was previously in human phase 1 clinical trials for the treatment of idiopathic pulmonary fibrosis and solid tumors.

omipalisib: inhibitor of mTOR protein
aromatic ether;
difluorobenzene;
pyridazines;
pyridines;
quinolines;
sulfonamide
anticoronaviral agent;
antineoplastic agent;
autophagy inducer;
EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor;
mTOR inhibitor;
radiosensitizing agent
gsk 1363089GSK 1363089: a multikinase inhibitor that acts on Met, RON, Axl, and VEGFR; structure in first sourcearomatic ether
osimertinibosimertinib : A member of the class of aminopyrimidines that is 4-(1-methylindol-3-yl)pyrimidin-2-amine in which one of the amino hydrogens is replaced by a 2-methoxy-4-[2-(dimethylamino)ethyl](methyl)amino-5-acrylamidophenyl group. Used (as the mesylate salt) for treatment of EGFR T790M mutation positive non-small cell lung cancer.

osimertinib: an EGFR tyrosine kinase inhibitor
acrylamides;
aminopyrimidine;
biaryl;
indoles;
monomethoxybenzene;
secondary amino compound;
secondary carboxamide;
substituted aniline;
tertiary amino compound
antineoplastic agent;
epidermal growth factor receptor antagonist