Summary: Dihydroorotate dehydrogenase
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Dihydroorotate dehydrogenase Edit Wikipedia article
Dihydroorotate dehydrogenase monomer + inhibitor, Human
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / QuickGO|
Dihydroorotate dehydrogenase from E. coli
|SCOPe||1dor / SUPFAM|
|Human dihydroorotate dehydrogenase|
|Locus||Chr. 16 q22|
Dihydroorotate dehydrogenase (DHODH) is an enzyme that in humans is encoded by the DHODH gene on chromosome 16. The protein encoded by this gene catalyzes the fourth enzymatic step, the ubiquinone-mediated oxidation of dihydroorotate to orotate, in de novo pyrimidine biosynthesis. This protein is a mitochondrial protein located on the outer surface of the inner mitochondrial membrane (IMM). Inhibitors of this enzyme are used to treat autoimmune diseases such as rheumatoid arthritis.
DHODH can vary in cofactor content, oligomeric state, subcellular localization, and membrane association. An overall sequence alignment of these DHODH variants presents two classes of DHODHs: the cytosolic Class 1 and the membrane-bound Class 2. In Class 1 DHODH, a basic cysteine residue catalyzes the oxidation reaction, whereas in Class 2, the serine serves this catalytic function. Structurally, Class 1 DHODHs can also be divided into two subclasses, one of which forms homodimers and uses fumarate as its electron acceptor, and the other which forms heterotetramers and uses NAD+ as its electron acceptor. This second subclass contains an addition subunit (PyrK) containing an iron-sulfur cluster and a flavin adenine dinucleotide (FAD). Meanwhile, Class 2 DHODHs use coenzyme Q/ubiquinones for their oxidant.
In higher eukaryotes, this class of DHODH contains an N-terminal bipartite signal comprising a cationic, amphipathic mitochondrial targeting sequence of about 30 residues and a hydrophobic transmembrane sequence. The targeting sequence is responsible for this proteinâ€™s localization to the IMM, possibly from recruiting the import apparatus and mediating Î”Î¨-driven transport across the inner and outer mitochondrial membranes, while the transmembrane sequence is essential for its insertion into the IMM. This sequence is adjacent to a pair of Î±-helices, Î±1 and Î±2, which are connected by a short loop. Together, this pair forms a hydrophobic funnel that is suggested to serve as the insertion site for ubiquinone, in conjunction with the FMN binding cavity at the C-terminal. The two terminal domains are directly connected by an extended loop. The C-terminal domain is the larger of the two and folds into a conserved Î±/Î²-barrel structure with a core of eight parallel Î²-strands surrounded by eight Î± helices.
Human DHODH is a ubiquitous FMN flavoprotein. In bacteria (gene pyrD), it is located on the inner side of the cytosolic membrane. In some yeasts, such as in Saccharomyces cerevisiae (gene URA1), it is a cytosolic protein, whereas, in other eukaryotes, it is found in the mitochondria. It is also the only enzyme in the pyrimidine biosynthesis pathway located in the mitochondria rather than the cytosol.
As an enzyme associated with the electron transport chain, DHODH links mitochondrial bioenergetics, cell proliferation, ROS production, and apoptosis in certain cell types. DHODH depletion also resulted in increased ROS production, decreased membrane potential and cell growth retardation. Also, due to its role in DNA synthesis, inhibition of DHODH may provide a means to regulate transcriptional elongation.