Target type: biologicalprocess
The chemical reactions and pathways resulting in the formation of thymidine, deoxyribosylthymine thymine 2-deoxyriboside, a deoxynucleoside very widely distributed but occurring almost entirely as phosphoric esters in deoxynucleotides and deoxyribonucleic acid, DNA. [GOC:go_curators]
Thymidine biosynthesis is a crucial metabolic pathway for the synthesis of thymidine, a deoxyribonucleoside essential for DNA replication and repair. This process occurs in the cytoplasm of cells and involves a series of enzymatic steps starting from the precursor molecule dihydrofolate.
1. **Tetrahydrofolate (THF) synthesis:** Dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate to tetrahydrofolate (THF), a coenzyme required for subsequent reactions.
2. **Serine hydroxymethyltransferase (SHMT) reaction:** Serine hydroxymethyltransferase (SHMT) converts serine to glycine and transfers a one-carbon unit from serine to THF, generating 5,10-methylene-THF.
3. **Thymidylate synthase (TS) reaction:** Thymidylate synthase (TS) catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) using 5,10-methylene-THF as a methyl donor. This reaction is the rate-limiting step in thymidine biosynthesis and a major target for cancer chemotherapy.
4. **Conversion to thymidine:** dTMP is further phosphorylated to dTDP and then to dTTP, the active form of thymidine incorporated into DNA.
**Regulation of Thymidine Biosynthesis:**
Thymidine biosynthesis is tightly regulated by various mechanisms:
- **Feedback inhibition:** The end product, dTTP, inhibits the activity of TS and other enzymes involved in the pathway.
- **Transcriptional regulation:** The expression of genes encoding enzymes involved in thymidine biosynthesis is regulated by transcription factors responding to cellular signals, such as growth factors and DNA damage.
- **Availability of substrates:** The availability of substrates like serine, glycine, and dihydrofolate influences the rate of thymidine biosynthesis.
**Importance of Thymidine Biosynthesis:**
Thymidine biosynthesis is essential for cell proliferation and growth as DNA replication requires a balanced supply of all four deoxyribonucleotides, including thymidine.
- **DNA replication:** The incorporation of thymidine into DNA is critical for maintaining genetic information and enabling cell division.
- **DNA repair:** Thymidine biosynthesis is also involved in DNA repair mechanisms, which are vital for maintaining genomic integrity.
- **Cancer therapy:** Thymidine biosynthesis is a crucial target for cancer chemotherapy, as rapidly dividing cancer cells rely heavily on this pathway for DNA replication. Drugs that inhibit key enzymes like DHFR and TS have been developed to specifically target cancer cell proliferation.
Overall, thymidine biosynthesis is a fundamental metabolic process with far-reaching implications for cell growth, DNA replication, and repair. Its dysregulation can lead to various diseases, including cancer, while its manipulation has become a critical aspect of cancer therapy.'
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| Protein | Definition | Taxonomy |
|---|---|---|
| Thymidylate kinase | A thymidylate kinase that is encoded in the genome of human. [PRO:DNx, UniProtKB:P23919] | Homo sapiens (human) |
| Thymidine kinase, cytosolic | A thymidine kinase, cytosolic that is encoded in the genome of human. [PRO:DNx, UniProtKB:P04183] | Homo sapiens (human) |
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| thymidine | pyrimidine 2'-deoxyribonucleoside | Escherichia coli metabolite; human metabolite; metabolite; mouse metabolite | |
| idoxuridine | organoiodine compound; pyrimidine 2'-deoxyribonucleoside | antiviral drug; DNA synthesis inhibitor | |
| bromodeoxyuridine | Bromodeoxyuridine: A nucleoside that substitutes for thymidine in DNA and thus acts as an antimetabolite. It causes breaks in chromosomes and has been proposed as an antiviral and antineoplastic agent. It has been given orphan drug status for use in the treatment of primary brain tumors. | pyrimidine 2'-deoxyribonucleoside | antimetabolite; antineoplastic agent |
| cytarabine | beta-D-arabinoside; monosaccharide derivative; pyrimidine nucleoside | antimetabolite; antineoplastic agent; antiviral agent; immunosuppressive agent | |
| dithionitrobenzoic acid | dithionitrobenzoic acid : An organic disulfide that results from the formal oxidative dimerisation of 2-nitro-5-thiobenzoic acid. An indicator used to quantify the number or concentration of thiol groups. Dithionitrobenzoic Acid: A standard reagent for the determination of reactive sulfhydryl groups by absorbance measurements. It is used primarily for the determination of sulfhydryl and disulfide groups in proteins. The color produced is due to the formation of a thio anion, 3-carboxyl-4-nitrothiophenolate. | nitrobenzoic acid; organic disulfide | indicator |
| thymidine monophosphate | dTMP : The neutral species of thymidine 5'-monophosphate (2'-deoxythymidine 5'-monophosphate). Thymidine Monophosphate: 5-Thymidylic acid. A thymine nucleotide containing one phosphate group esterified to the deoxyribose moiety. | thymidine 5'-monophosphate | fundamental metabolite |
| deoxyuridine | pyrimidine 2'-deoxyribonucleoside | Escherichia coli metabolite; human metabolite; mouse metabolite; Saccharomyces cerevisiae metabolite | |
| 2'-deoxyadenosine | 2'-deoxyformycin A: RN not in Chemline 9/85; RN and structure given in first source | purine 2'-deoxyribonucleoside; purines 2'-deoxy-D-ribonucleoside | Escherichia coli metabolite; human metabolite; mouse metabolite; Saccharomyces cerevisiae metabolite |
| stavudine | stavudine : A nucleoside analogue obtained by formal dehydration across positions 2 and 3 of thymidine. An inhibitor of HIV-1 reverse transcriptase Stavudine: A dideoxynucleoside analog that inhibits reverse transcriptase and has in vitro activity against HIV. | dihydrofuran; nucleoside analogue; organic molecular entity | antimetabolite; antiviral agent; EC 2.7.7.49 (RNA-directed DNA polymerase) inhibitor |
| vidarabine | adenine arabinoside : A purine nucleoside in which adenine is attached to arabinofuranose via a beta-N(9)-glycosidic bond. | beta-D-arabinoside; purine nucleoside | antineoplastic agent; bacterial metabolite; nucleoside antibiotic |
| zidovudine | zidovudine : A pyrimidine 2',3'-dideoxyribonucleoside compound having a 3'-azido substituent and thymine as the nucleobase. Zidovudine: A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by an azido group. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. The compound is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA during reverse transcription. It improves immunologic function, partially reverses the HIV-induced neurological dysfunction, and improves certain other clinical abnormalities associated with AIDS. Its principal toxic effect is dose-dependent suppression of bone marrow, resulting in anemia and leukopenia. | azide; pyrimidine 2',3'-dideoxyribonucleoside | antimetabolite; antiviral drug; HIV-1 reverse transcriptase inhibitor |
| fialuridine | |||
| thymine arabinoside | thymine arabinoside: selectively inhibits replication of herpes simplex virus | N-glycosyl compound | |
| 2'-deoxyuridylic acid | 2'-deoxyuridylic acid: RN given refers to parent cpd | deoxyuridine phosphate; pyrimidine 2'-deoxyribonucleoside 5'-monophosphate | Escherichia coli metabolite; metabolite; mouse metabolite |
| 2',3'-didehydro-2',3'-dideoxyuridine | |||
| 3'-azido-3'-deoxythymidine 5'phosphate | 3'-azido-3'-deoxythymidine 5'phosphate: inhibits thymidylate kinase | ||
| clevudine | |||
| bromodeoxyuridylate | bromodeoxyuridylate: RN given refers to parent cpd | ||
| 5-propyl-2'-deoxyuridine | 5-propyl-2'-deoxyuridine: RN given refers to parent cpd | ||
| 5'-o-dimethyltritylthymidine | |||
| 1-(2-deoxy-2-fluoroarabinofuranosyl)-5-ethyluracil | 1-(2-deoxy-2-fluoroarabinofuranosyl)-5-ethyluracil: RN given refers to (beta-D)-isomer; structure given in first source | ||
| (north)-methanocarbathymidine | (north)-methanocarbathymidine: also called NMCT 1-[(1S,2S,4S,5R)-4-hydroxy-5-(hydroxymethyl)bicyclo[3.1.0]hexan-2-yl]thymine : A carbobicyclic compound that is bicyclo[3.1.0]hexane which is substituted at the 2-pro-S, 4-pro-S and 5-pro-R positions by thymin-1-yl, hydroxy, and hydroxymethyl groups, respectively. | C-glycosyl pyrimidine; carbobicyclic compound; primary alcohol; pyrimidone; secondary alcohol | |
| brivudine | brivudine: anti-herpes agent | ||
| carbocyclic 5-iodo-2'-deoxyuridine | |||
| 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine | 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine: a highly active anti-HIV agent; structure in first source | ||
| deoxy-4-thiothymidine | 4-thiothymidine: structure in first source | ||
| sorivudine | organic molecular entity | ||
| acyclovir | acyclovir : An oxopurine that is guanine substituted by a (2-hydroxyethoxy)methyl substituent at position 9. Used in the treatment of viral infections. Acyclovir: A GUANOSINE analog that acts as an antimetabolite. Viruses are especially susceptible. Used especially against herpes. | 2-aminopurines; oxopurine | antimetabolite; antiviral drug |
| deoxyguanosine | purine 2'-deoxyribonucleoside; purines 2'-deoxy-D-ribonucleoside | Escherichia coli metabolite; human metabolite; mouse metabolite; Saccharomyces cerevisiae metabolite | |
| 9-(4-hydroxybutyl)guanine | |||
| 9-arabinofuranosylguanine | 9-arabinofuranosylguanine: RN given refers to (beta)-isomer 9-beta-D-arabinofuranosylguanine : A purine nucleoside in which guanine is attached to arabinofuranose via a beta-N(9)-glycosidic bond. It inhibits DNA synthesis and causes cell death. | beta-D-arabinoside; purine nucleoside | antineoplastic agent; DNA synthesis inhibitor |