Enzymes are proteins that facilitate chemical reactions, acting as biological catalysts to speed up processes without being consumed. Dihydroorotate Dehydrogenase, known as DHODH, plays a distinct role in cellular metabolism. Its activity is regulated and can be influenced by specific molecules called inhibitors. These inhibitors modulate biological pathways for therapeutic benefit.
Understanding DHODH: The Enzyme’s Role
Dihydroorotate dehydrogenase (DHODH) is an enzyme in the inner mitochondrial membrane of human cells. This enzyme performs a specific step in the de novo pyrimidine synthesis pathway, where cells create new pyrimidine nucleotides from simpler precursors. Pyrimidines are fundamental building blocks for deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), making them indispensable for cell division and growth.
The reaction catalyzed by DHODH converts dihydroorotate to orotate. This conversion is the fourth step in pyrimidine synthesis and the only one occurring in the mitochondria, linking it to cellular energy production. DHODH utilizes ubiquinone as an electron acceptor during this oxidation process.
This enzymatic reaction is a rate-limiting step in the de novo pyrimidine synthesis pathway, directly controlling the speed of new pyrimidine production. Rapidly dividing cells, such as those in the immune system or in tumors, have a high demand for DNA and RNA components, making DHODH’s activity important for their sustained proliferation.
How DHODH Inhibitors Work
DHODH inhibitors are molecules designed to specifically interfere with the function of the DHODH enzyme. These compounds bind to the enzyme’s active or quinone-binding sites, where the enzyme normally interacts with substrates to catalyze the reaction. By occupying these sites, the inhibitors physically block the enzyme’s ability to convert dihydroorotate to orotate.
This direct inhibition of DHODH leads to a significant disruption in the de novo pyrimidine synthesis pathway. With orotate production reduced, subsequent pathway steps, leading to uridine monophosphate (UMP) and other pyrimidine nucleotides, are severely limited. A shortage of these nucleotides then directly impacts a cell’s ability to synthesize new DNA and RNA.
Cells that are rapidly dividing, such as hyperactive immune cells or cancer cells, are particularly susceptible to this disruption because they have a constant and high demand for new genetic material. By limiting the availability of pyrimidine building blocks, DHODH inhibitors can effectively halt the cell cycle and, in some cases, induce programmed cell death in these fast-growing cells. Normal, non-dividing cells, with lower metabolic demands, are generally less affected by DHODH inhibition, allowing for selective targeting.
Therapeutic Applications of DHODH Inhibitors
DHODH inhibitors have found significant therapeutic applications, particularly in conditions characterized by uncontrolled or excessive cell proliferation. Their ability to selectively target cells with high metabolic activity makes them valuable in several medical fields.
In autoimmune diseases, such as multiple sclerosis (MS) and rheumatoid arthritis (RA), the immune system mistakenly attacks the body’s own tissues. This involves over-proliferation of immune cells, like lymphocytes. DHODH inhibitors, such as leflunomide for rheumatoid arthritis and its active metabolite teriflunomide for multiple sclerosis, work by reducing the proliferation of these hyperactive immune cells, thereby dampening the autoimmune response and alleviating symptoms.
DHODH inhibitors are also being investigated for their potential in oncology. Cancer cells’ rapid, uncontrolled division requires a substantial supply of pyrimidine nucleotides for DNA and RNA synthesis. By inhibiting DHODH, these compounds can starve cancer cells of the necessary building blocks, thereby inhibiting tumor growth and potentially sensitizing them to other chemotherapy agents. Preclinical and clinical studies explore their use in various cancers, including acute myeloid leukemia, multiple myeloma, and breast cancer.
Beyond autoimmune conditions and cancer, DHODH inhibitors show emerging promise in combating viral infections. Many viruses rely on the host cell’s pyrimidine synthesis pathway to replicate their own genetic material. By blocking DHODH, these inhibitors can interfere with viral replication, reducing the viral load and infection. This includes potential applications against viruses like SARS-CoV-2 and Epstein-Barr virus (EBV), with research indicating they can prevent EBV reactivation.