On Dihydroorotate Dehydrogenases and Their Inhibitors and Uses

• Published in: Journal of medicinal chemistry Vol. 56; no. 8; pp. 3148 - 3167
• Main Authors: Munier-Lehmann, Hélène, Vidalain, Pierre-Olivier, Tangy, Frédéric, Janin, Yves L
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 25-04-2013
• Subjects: Animals; Bacteria - enzymology; Coccidia - enzymology; Coccidiostats - therapeutic use; Enzyme Inhibitors - therapeutic use; Humans; Life Sciences; Microbiology and Parasitology; Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors; Oxidoreductases Acting on CH-CH Group Donors - chemistry; Oxidoreductases Acting on CH-CH Group Donors - genetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm301848w

Proper nucleosides availability is crucial for the proliferation of living entities (eukaryotic cells, parasites, bacteria, and virus). Accordingly, the uses of inhibitors of the de novo nucleosides biosynthetic pathways have been investigated in the past. In the following we have focused on dihydroorotate dehydrogenase (DHODH), the fourth enzyme in the de novo pyrimidine nucleosides biosynthetic pathway. We first described the different types of enzyme in terms of sequence, structure, and biochemistry, including the reported bioassays. In a second part, the series of inhibitors of this enzyme along with a description of their potential or actual uses were reviewed. These inhibitors are indeed used in medicine to treat autoimmune diseases such as rheumatoid arthritis or multiple sclerosis (leflunomide and teriflunomide) and have been investigated in treatments of cancer, virus, and parasite infections (i.e., malaria) as well as in crop science.