Pyrimidine Degradation

1. 1

   UMP → uridine

   5'-Nucleotidase (NT5C/NT5E) 3.1.3.5 ST-0238 Irreversible/directional H2O Pi
   In UMP

   Out Uridine
   › Notes

   5′-Nucleotidase catalyzes UMP + H2O → uridine + Pi. CMP, TMP, and their deoxy counterparts are likewise dephosphorylated by nucleotide phosphatases/nucleotidases before nucleoside or base breakdown.

2. 2

   CMP (or cytidine) → uridine

   Cytidine deaminase 3.5.4.5 ST-0239 Irreversible/directional H2O
   In CMP

   Out Uridine
   › Notes

   Cytidine deaminase catalyzes cytidine + H2O → uridine + NH3; after CMP is dephosphorylated, this reaction funnels cytosine nucleosides into uracil catabolism. Cytidine deaminase also acts on deoxycytidine to form deoxyuridine and is clinically important in nucleoside drug metabolism.

3. 3

   Uridine → uracil

   Uridine phosphorylase 2.4.2.3 ST-0240 Irreversible/directional Pi
   In Uridine

   Out Uracil
   › Notes

   Uridine phosphorylase catalyzes uridine + Pi ⇌ uracil + ribose 1-phosphate. Deoxyuridine can similarly be phosphorolyzed to uracil plus deoxyribose 1-phosphate.

4. 4

   TMP → thymidine

   5'-Nucleotidase (NT5C/NT5E) 3.1.3.5 ST-0241 Irreversible/directional H2O Pi
   In dTMP

   Out Thymidine
   › Notes

   5′-Nucleotidase catalyzes TMP + H2O → thymidine + Pi.

5. 5

   Thymidine → thymine

   Thymidine phosphorylase 2.4.2.4 ST-0242 Irreversible/directional Pi
   In Thymidine

   Out Thymine
   › Notes

   Thymidine phosphorylase catalyzes thymidine + Pi ⇌ thymine + 2-deoxyribose 1-phosphate. The reaction also participates in thymidine salvage, depending on metabolite concentrations.

6. 6

   Uracil → 5,6-dihydrouracil

   Dihydropyrimidine dehydrogenase (DPD) 1.3.1.2 ST-0243 Irreversible/directional rate-limiting NADP+ NADPH
   In Uracil

   Out 5,6-Dihydrouracil
   › Notes

   DPD catalyzes uracil + NADPH + H+ → 5,6-dihydrouracil + NADP+. DPD is a large flavoprotein/iron-sulfur enzyme requiring FAD, FMN, and NADPH; this NADPH-dependent reduction is the rate-limiting step of pyrimidine degradation.

7. 7

   Thymine → 5,6-dihydrothymine

   Dihydropyrimidine dehydrogenase (DPD) 1.3.1.2 ST-0244 Irreversible/directional rate-limiting NADP+ NADPH
   In Thymine

   Out 5,6-Dihydrothymine
   › Notes

   DPD catalyzes thymine + NADPH + H+ → 5,6-dihydrothymine + NADP+. The same rate-limiting enzyme handles both major pyrimidine bases.

8. 8

   5,6-Dihydrouracil → N-carbamyl-beta-alanine

   Dihydropyrimidinase 3.5.2.2 ST-0245 Irreversible/directional H2O
   In 5,6-Dihydrouracil

   Out N-Carbamyl-beta-alanine
   › Notes

   Dihydropyrimidinase hydrolyzes the reduced ring: 5,6-dihydrouracil + H2O → N-carbamyl-beta-alanine. This metalloenzyme opens the pyrimidine ring.

9. 9

   5,6-Dihydrothymine → N-carbamyl-beta-aminoisobutyrate

   Dihydropyrimidinase 3.5.2.2 ST-0246 Irreversible/directional H2O
   In 5,6-Dihydrothymine

   Out N-Carbamyl-beta-aminoisobutyrate
   › Notes

   Dihydropyrimidinase catalyzes 5,6-dihydrothymine + H2O → N-carbamyl-beta-aminoisobutyrate.

10. 10

    N-Carbamyl-beta-alanine → beta-alanine

    Beta-ureidopropionase 3.5.1.6 ST-0247 Irreversible/directional H2O
    In N-Carbamyl-beta-alanine

    Out beta-Alanine
    › Notes

    Beta-ureidopropionase catalyzes N-carbamyl-beta-alanine + H2O → beta-alanine + NH3 + CO2. This completes the uracil-derived ring-carbon/nitrogen disposal sequence.

11. 11

    N-Carbamyl-beta-aminoisobutyrate → beta-aminoisobutyrate

    Beta-ureidopropionase 3.5.1.6 ST-0248 Irreversible/directional H2O
    In N-Carbamyl-beta-aminoisobutyrate

    Out beta-Aminoisobutyrate
    › Notes

    Beta-ureidopropionase catalyzes N-carbamyl-beta-aminoisobutyrate + H2O → beta-aminoisobutyrate + NH3 + CO2.

12. 12

    Beta-alanine → malonate semialdehyde → acetyl-CoA

    ↪ malonate semialdehyde → acetyl-CoA

    Beta-alanine transaminase (AGXT2) 2.6.1.19 ST-0249 Irreversible/directional
    In beta-Alanine

    Out Malonate semialdehyde
    › Notes

    Beta-alanine transaminase (largely AGXT2-associated activity) transfers the amino group of beta-alanine to an alpha-ketoacid acceptor, producing malonate semialdehyde. Malonate-semialdehyde dehydrogenase (ALDH6A1) then catalyzes oxidative decarboxylation of malonate semialdehyde with CoA and NAD+ to form acetyl-CoA, CO2, and NADH; exact transaminase partners vary by tissue.

13. 13

    Beta-aminoisobutyrate → methylmalonate semialdehyde → propionyl-CoA

    ↪ methylmalonate semialdehyde → propionyl-CoA

    Beta-aminoisobutyrate transaminase 2.6.1.40 ST-0250 Irreversible/directional NAD+ NADH
    In beta-Aminoisobutyrate

    Out Methylmalonate semialdehyde
    › Notes

    Beta-aminoisobutyrate transaminase generates methylmalonate semialdehyde, which methylmalonate-semialdehyde dehydrogenase (ALDH6A1) converts using CoA and NAD+ to propionyl-CoA + CO2 + NADH.

14. 14

    Propionyl-CoA → succinyl-CoA

    Propionyl-CoA carboxylase 6.4.1.3 ST-0251 Irreversible/directional ATP Biotin (B7) Cobalamin (B12) Bicarbonate/CO2
    In Propionyl-CoA

    Out Succinyl-CoA
    › Notes

    Propionyl-CoA carboxylase uses ATP, bicarbonate, and biotin to convert propionyl-CoA to D-methylmalonyl-CoA; methylmalonyl-CoA epimerase produces L-methylmalonyl-CoA; and adenosylcobalamin-dependent methylmalonyl-CoA mutase rearranges it to succinyl-CoA. These downstream steps permit thymine carbon to enter the tricarboxylic acid cycle.

Showing all 14 steps.

Overview

Pyrimidine nucleotides are degraded to highly water-soluble, small metabolites rather than to a poorly soluble terminal product such as urate. Uracil yields beta-alanine, whereas thymine yields beta-aminoisobutyrate; the carbon skeletons can enter central metabolism. Cytosine is first deaminated at the nucleoside level in humans, so its degradation converges with the uracil pathway.

Cellular location

Initial nucleotidase, nucleoside phosphorylase, and deaminase reactions occur mainly in the cytosol. The reductive ring-opening pathway is primarily hepatic but is also present in other tissues; the first enzyme, dihydropyrimidine dehydrogenase (DPD), is associated with the cytosolic face of the endoplasmic reticulum. Subsequent catabolic products are handled in cytosolic and mitochondrial reactions, with liver and kidney important for nitrogen disposal and further oxidation.

Net energetics

Conversion of uracil or thymine to the corresponding dihydropyrimidine consumes one NADPH at the DPD step; ring opening and carbamyl-group hydrolysis do not directly consume ATP. Subsequent oxidation of malonate or methylmalonate semialdehyde produces NADH and activated acyl-CoA products. Complete entry of thymine-derived propionyl-CoA into the tricarboxylic acid cycle requires one ATP → ADP equivalent at propionyl-CoA carboxylase and adenosylcobalamin for methylmalonyl-CoA mutase.

Clinical significance

Pyrimidine degradation prevents accumulation of bases/nucleosides and recovers their carbon skeletons as acetyl-CoA or succinyl-CoA, unlike purine catabolism, which terminates at urate. DPD is the major enzyme that catabolizes 5-fluorouracil; partial or complete DPD deficiency can cause life-threatening fluoropyrimidine toxicity, including severe mucositis, diarrhea, cytopenias, and neurotoxicity, at standard doses. Dihydropyrimidinase and beta-ureidopropionase deficiencies are rare inborn errors associated with variable neurologic manifestations and abnormal urinary pyrimidine metabolites. Elevated beta-aminoisobutyrate excretion may occur with increased thymine turnover or metabolic variation.