The dihydroorotate dehydrogenases: Past and present

Arch Biochem Biophys. 2017 Oct 15;632:175-191. doi: 10.1016/j.abb.2017.06.019. Epub 2017 Jun 27.

Abstract

The flavoenzyme dihydroorotate dehydrogenase catalyzes the stereoselective oxidation of (S)-dihydroorotate to orotate in the fourth of the six conserved enzymatic reactions involved in the de novo pyrimidine biosynthetic pathway. Inhibition of pyrimidine metabolism by selectively targeting DHODHs has been exploited in the development of new therapies against cancer, immunological disorders, bacterial and viral infections, and parasitic diseases. Through a chronological narrative, this review summarizes the efforts of the scientific community to achieve our current understanding of structural and biochemical properties of DHODHs. It also attempts to describe the latest advances in medicinal chemistry for therapeutic development based on the selective inhibition of DHODH, including an overview of the experimental techniques used for ligand screening during the process of drug discovery.

Keywords: Dihydroorotate dehydrogenase; Drug target; Flavoenzyme; Pyrimidine biosynthesis.

Publication types

  • Review

MeSH terms

  • Animals
  • Bacterial Infections / drug therapy
  • Bacterial Infections / enzymology
  • Dihydroorotate Dehydrogenase
  • Drug Discovery
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / therapeutic use
  • Flavoproteins* / antagonists & inhibitors
  • Flavoproteins* / chemistry
  • Flavoproteins* / metabolism
  • Humans
  • Immune System Diseases / drug therapy
  • Immune System Diseases / enzymology
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Oxidoreductases Acting on CH-CH Group Donors* / antagonists & inhibitors
  • Oxidoreductases Acting on CH-CH Group Donors* / chemistry
  • Oxidoreductases Acting on CH-CH Group Donors* / metabolism
  • Parasitic Diseases / drug therapy
  • Parasitic Diseases / enzymology
  • Pyrimidines / chemistry
  • Pyrimidines / metabolism
  • Virus Diseases / drug therapy
  • Virus Diseases / enzymology

Substances

  • Dihydroorotate Dehydrogenase
  • Enzyme Inhibitors
  • Flavoproteins
  • Pyrimidines
  • Oxidoreductases Acting on CH-CH Group Donors