Dihydroorotate dehydrogenase (DHODH)

Class

DHODH inhibitor

Dihydroorotate dehydrogenase (DHODH) is an enzyme located in the inner mitochondrial membrane that carries out a key step in the de novo synthesis of pyrimidines, the class of building blocks (including uracil and cytosine derivatives) needed to make RNA and DNA. Most cells can obtain pyrimidines either by synthesizing them from scratch or by recycling existing bases through a salvage pathway. Rapidly dividing or newly activated cells, such as proliferating lymphocytes in autoimmune disease, place unusually high demand on the de novo route because salvage alone cannot keep pace with their nucleotide needs. By inhibiting DHODH, a drug can selectively limit the proliferative burst of these activated immune cells while sparing resting cells that rely mainly on salvage pathways. This rationale underlies the use of DHODH inhibition in autoimmune and inflammatory conditions, where dampening lymphocyte expansion helps reduce disease activity. The same logic extends to certain cancers and infectious organisms that are similarly dependent on rapid pyrimidine turnover. Because the enzyme sits at a metabolic chokepoint shared by many cell types, its inhibition is a broadly applicable but not perfectly selective strategy, and its clinical value depends on the balance between suppressing pathological proliferation and preserving normal tissue turnover.