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dTMP biosynthetic process

Definition

Target type: biologicalprocess

The chemical reactions and pathways resulting in the formation of dTMP, deoxyribosylthymine monophosphate (2'-deoxyribosylthymine 5'-phosphate). [ISBN:0198506732]

The biosynthesis of dTMP (deoxythymidine monophosphate) is a crucial step in DNA replication, ensuring the correct incorporation of thymine bases into the newly synthesized DNA strands. The process starts with the conversion of dUMP (deoxyuridine monophosphate) to dTMP, catalyzed by the enzyme thymidylate synthase (TS). This reaction involves a one-carbon unit transfer from tetrahydrofolate (THF) to dUMP, forming dTMP and dihydrofolate (DHF). THF acts as a carrier of one-carbon units, and its reduced form, dihydrofolate (DHF), is required for the reaction. The enzyme TS utilizes a unique catalytic mechanism, involving a covalent intermediate with dUMP, facilitating the transfer of the one-carbon unit from THF. This process requires the presence of methylenetetrahydrofolate reductase (MTHFR), which converts dihydrofolate back to tetrahydrofolate, allowing the cycle to continue. The dTMP produced is then incorporated into DNA by DNA polymerase, replacing dUMP with dTMP in the growing DNA strand. The dTMP biosynthesis pathway is a critical target for anticancer drugs, as inhibiting TS can effectively prevent DNA replication and cell growth. Several drugs, like methotrexate and 5-fluorouracil, act by inhibiting different steps in this pathway. These drugs disrupt the supply of dTMP, halting cell proliferation and demonstrating the importance of dTMP biosynthesis in maintaining cellular function.'
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Proteins (5)

ProteinDefinitionTaxonomy
Thymidylate synthaseA thymidylate synthase that is encoded in the genome of Escherichia coli K-12. [OMA:P0A884, PRO:DNx]Escherichia coli K-12
Thymidylate synthaseA thymidylate synthase that is encoded in the genome of Escherichia coli K-12. [OMA:P0A884, PRO:DNx]Escherichia coli K-12
Serine hydroxymethyltransferase, cytosolicA serine hydroxymethyltransferase, cytosolic that is encoded in the genome of human. [PRO:DNx, UniProtKB:P34896]Homo sapiens (human)
Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrialA deoxyuridine 5-triphosphate nucleotidohydrolase, mitochondrial that is encoded in the genome of human. [PRO:DNx, UniProtKB:P33316]Homo sapiens (human)
Thymidylate synthaseA thymidylate synthase that is encoded in the genome of human. [PRO:DNx, UniProtKB:P04818]Homo sapiens (human)

Compounds (26)

CompoundDefinitionClassesRoles
phenolphthaleinPhenolphthalein: An acid-base indicator which is colorless in acid solution, but turns pink to red as the solution becomes alkaline. It is used medicinally as a cathartic.phenols
trimethoprimtrimethoprim : An aminopyrimidine antibiotic whose structure consists of pyrimidine 2,4-diamine and 1,2,3-trimethoxybenzene moieties linked by a methylene bridge.

Trimethoprim: A pyrimidine inhibitor of dihydrofolate reductase, it is an antibacterial related to PYRIMETHAMINE. It is potentiated by SULFONAMIDES and the TRIMETHOPRIM, SULFAMETHOXAZOLE DRUG COMBINATION is the form most often used. It is sometimes used alone as an antimalarial. TRIMETHOPRIM RESISTANCE has been reported.
aminopyrimidine;
methoxybenzenes
antibacterial drug;
diuretic;
drug allergen;
EC 1.5.1.3 (dihydrofolate reductase) inhibitor;
environmental contaminant;
xenobiotic
1,8-naphthalenedicarboxylic acid anhydride1,8-naphthalenedicarboxylic acid anhydride: used as seed protector from herbicidescyclic dicarboxylic anhydride
fluorodeoxyuridylateFluorodeoxyuridylate: 5-Fluoro-2'-deoxyuridylate. An inhibitor of thymidylate synthetase. Formed from 5-fluorouracil or 5-fluorodeoxyuridine.pyrimidine 2'-deoxyribonucleoside 5'-monophosphate
2'-deoxyuridylic acid2'-deoxyuridylic acid: RN given refers to parent cpddeoxyuridine phosphate;
pyrimidine 2'-deoxyribonucleoside 5'-monophosphate
Escherichia coli metabolite;
metabolite;
mouse metabolite
2',3'-didehydro-2',3'-dideoxyuridine
dansyl hydrazine
methotrexatedicarboxylic acid;
monocarboxylic acid amide;
pteridines
abortifacient;
antimetabolite;
antineoplastic agent;
antirheumatic drug;
dermatologic drug;
DNA synthesis inhibitor;
EC 1.5.1.3 (dihydrofolate reductase) inhibitor;
immunosuppressive agent
n-(4-(n-((2,4-diaminofuro(2,3-d)pyrimidin-5-yl)methyl)amino)benzoyl)glutamic acidN-(4-(N-((2,4-diaminofuro(2,3-d)pyrimidin-5-yl)methyl)amino)benzoyl)glutamic acid: structure given in first source
n-4-hydroxy-2'-deoxycytidylic acidN-4-hydroxy-2'-deoxycytidylic acid: reversibly binds to thymidylate synthetase
flavin mononucleotideflavin mononucleotide;
vitamin B2
bacterial metabolite;
coenzyme;
cofactor;
human metabolite;
mouse metabolite
folic acidfolcysteine: used to promote fertility in chickens

vitamin B9 : Any B-vitamin that exhibits biological activity against vitamin B9 deficiency. Vitamin B9 refers to the many forms of folic acid and its derivatives, including tetrahydrofolic acid (the active form), methyltetrahydrofolate (the primary form found in blood), methenyltetrahydrofolate, folinic acid amongst others. They are present in abundance in green leafy vegetables, citrus fruits, and animal products. Lack of vitamin B9 leads to anemia, a condition in which the body cannot produce sufficient number of red blood cells. Symptoms of vitamin B9 deficiency include fatigue, muscle weakness, and pale skin.
folic acids;
N-acyl-amino acid
human metabolite;
mouse metabolite;
nutrient
raltitrexedN-acyl-amino acid
nolatrexednolatrexed: structure given in first source; RN given refers to dihydrochloride
ici 198583ICI 198583: RN & structure given in first source
n-(4(n-((2-amino-4-hydroxy-6-quinazolinyl)methyl)prop-2-ynylamino)benzoyl)-l-glutamic acid
1843u891843U89: structure given in first source; a folate analog
5,11-methenyltetrahydrohomofolate
pemetrexedpemetrexed disodium : An organic sodium salt that is the disodium salt of N-{4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamic acid. Inhibits thymidylate synthase (TS), 421 dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT).N-acyl-L-glutamic acid;
pyrrolopyrimidine
antimetabolite;
antineoplastic agent;
EC 1.5.1.3 (dihydrofolate reductase) inhibitor;
EC 2.1.1.45 (thymidylate synthase) inhibitor;
EC 2.1.2.2 (phosphoribosylglycinamide formyltransferase) inhibitor
n(10)-methylfolatefolic acids
cb 3717N-acyl-L-glutamic acid
cb 30865
ag 85AG 85: structure given in first source
cb 3705CB 3705: inhibitor of dihydrofolate reductase & thymidylate synthetase
2-desamino-2-methyl-5,8-dideazaisofolic acid2-desamino-2-methyl-5,8-dideazaisofolic acid: structure given in first source
(5)n,(8)n-deaza-(10)-n-methylfolate(5)N,(8)N-deaza-(10)-N-methylfolate: structure