thymine

**Structure & identity** - Pyrimidine (single-ring) base, i.e., 5-methyluracil. Pyrimidines: Cytosine, Uracil, Thymine ("CUT the Py"). Thymine has a methyl group at C5 that uracil lacks. - Found in DNA; uracil replaces it in RNA. Pairs with adenine through 2 H-bonds (G≡C has 3, so GC-rich DNA has a higher melting temperature). - Nucleoside: thymidine. Nucleotide: thymidine monophosphate (dTMP).

**Why DNA uses thymine instead of uracil** - Cytosine spontaneously deaminates to uracil. If DNA normally contained uracil, repair enzymes could not tell a deaminated cytosine from a native base. - Because DNA normally contains thymine, uracil in DNA is recognized as damage. Uracil DNA glycosylase (base excision repair) removes it, then AP endonuclease, lyase, DNA polymerase β, and ligase finish the repair. - 5-methylcytosine deamination gives thymine directly. This is a common mutation hotspot at CpG sites, and the resulting mismatch is harder to repair.

**Synthesis (de novo pyrimidine pathway)** - Pyrimidines are made first as orotic acid, then attached to PRPP (the reverse of purine synthesis, where the base is built on the PRPP scaffold). CPS II (cytosolic, uses glutamine) is the rate-limiting enzyme. Aspartate transcarbamoylase and dihydroorotase are also involved. - Ribonucleotide reductase converts UDP to dUDP. dUDP becomes dUMP. - **Thymidylate synthase** converts dUMP to dTMP, using N5,N10-methylene-THF as the methyl donor. The THF is oxidized to DHF, then regenerated by dihydrofolate reductase (DHFR).

**Clinical correlations / drugs** - **5-Fluorouracil (5-FU)** and capecitabine: the metabolite FdUMP covalently inhibits thymidylate synthase, causing "thymineless death." Leucovorin enhances this by stabilizing the enzyme–FdUMP–folate complex. - **Methotrexate** (also trimethoprim in bacteria, pyrimethamine in protozoa): inhibits DHFR, which reduces THF and so reduces dTMP and purine synthesis. - **Hydroxyurea** inhibits ribonucleotide reductase, which lowers dNTP supply. - **Megaloblastic anemia** from B12 or folate deficiency: impaired thymidine synthesis causes defective DNA synthesis with preserved RNA/protein synthesis, which causes nuclear–cytoplasmic asynchrony and macro-ovalocytes. - **Orotic aciduria**: UMP synthase defect. It causes megaloblastic anemia that does not respond to B12 or folate, with normal ammonia and no hyperammonemia. Treat with uridine. - **OTC deficiency** also raises orotic acid, but it comes with hyperammonemia. - **Thymine dimers** (UV-induced, between adjacent thymines) cause xeroderma pigmentosum when nucleotide excision repair is defective (UvrABC exinuclease in bacteria; XP proteins in humans). Patients have extreme photosensitivity and a high risk of skin cancers. - **Lesch-Nyhan syndrome** involves purines (HGPRT deficiency), not pyrimidines, so don't confuse the two. - Thymine catabolism produces β-aminoisobutyrate, then succinyl-CoA. Purine catabolism produces uric acid.

**High-yield mnemonics** - "CUT the Py" (pyrimidines: C, U, T). "PURe As Gold" (purines: A, G). - DNA has T; RNA has U.