Biochemistry · Enzyme
Dihydroorotate dehydrogenase (DHODH) !
The only mitochondrial enzyme of pyrimidine synthesis; leflunomide, used in rheumatoid arthritis, blocks it.
Updated 2026-11-01
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Key facts
- Dihydroorotate + ubiquinone → orotate + ubiquinol.
- It sits on the outer face of the inner mitochondrial membrane and uses FMN.
- It passes electrons to coenzyme Q, linking pyrimidine synthesis with the respiratory chain.
- Teriflunomide (leflunomide's active metabolite) occupies the ubiquinone tunnel.
Regulation
- Depends on dihydroorotate and oxidised ubiquinone supply; it slows when the respiratory chain fails.
Inhibitors and toxins
- Leflunomide / teriflunomide
- Brequinar
Clinical notes
- Leflunomide restrains activated T cells, which need many pyrimidines: it is used in rheumatoid arthritis.
- Teriflunomide is used in multiple sclerosis; both are teratogenic.
- DHODH variants cause Miller syndrome, with facial and limb malformations.
Drugs that act here
Pathways
Related conditions
Related
Test yourself
Think of the answer, then tap the question to see it.
Where is dihydroorotate dehydrogenase, and where do its electrons go?
In the inner mitochondrial membrane; its electrons go to ubiquinone (coenzyme Q) of the respiratory chain.
How does leflunomide work in rheumatoid arthritis?
Its metabolite inhibits DHODH and starves activated T cells of pyrimidines, so they stop proliferating.
Which product does DHODH form?
Orotate (orotic acid), which then receives ribose phosphate from PRPP.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: DHODH: Dihydroorotate dehydrogenase (quinone), mitochondrial (human) (UniProt, 2026); 1D3H: HUMAN DIHYDROOROTATE DEHYDROGENASE COMPLEXED WITH ANTIPROLIFERATIVE AGENT A771726 (RCSB Protein Data Bank, 2026); Leflunomide: MedlinePlus Drug Information (MedlinePlus, US National Library of Medicine, 2026); Pyrimidine biosynthesis (Reactome, 2026).
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