These enzymes differ from class 1 dihydroorotate dehydrogenases (DHODH) on the electron acceptor, on their structure, and on their cellular localization. Since the reaction catalyzed by DHOQOs is both part of the
electron transport chain and the
pyrimidine de novo synthesis, it has been explored as a possible target for cancer treatment, immunological disorders and bacterial/viral infections.[6][7][8]
Structure
DHOQO structure colored by domains: N-terminal (blue) and core domain (green).
Structurally, DHOQOs are organized in monomers which adopt a (βα)8 (eightfold beta alpha barrel) fold.[9] The enzyme can be separated in its N-terminal domain (blue in the figure) and in its C-terminal domain (green in the figure).
The N-terminal domain is composed of two amphipathic α-helices (αA – αB) which are responsible for the
lipid membrane interaction. This region of the protein is also thought to mediate quinone binding.
Regarding the C-terminal domain, much of its structural elements are shared with the soluble counterparts of DHOQOs. This domain is responsible for the binding of the cofactor
FMN (making these enzymes part of the
Flavoprotein super-family) and the electron donor
dihydroorotate, close to the 8 β-strand core.
There are currently crystallographic structures of DHOQOs from 5 different organisms:
^Bader B, Knecht W, Fries M, Löffler M (August 1998). "Expression, purification, and characterization of histidine-tagged rat and human flavoenzyme dihydroorotate dehydrogenase". Protein Expression and Purification. 13 (3): 414–22.
doi:
10.1006/prep.1998.0925.
PMID9693067.
^Fagan RL, Nelson MN, Pagano PM, Palfey BA (December 2006). "Mechanism of flavin reduction in class 2 dihydroorotate dehydrogenases". Biochemistry. 45 (50): 14926–32.
doi:
10.1021/bi060919g.
PMID17154530.
^Björnberg O, Grüner AC, Roepstorff P, Jensen KF (March 1999). "The activity of Escherichia coli dihydroorotate dehydrogenase is dependent on a conserved loop identified by sequence homology, mutagenesis, and limited proteolysis". Biochemistry. 38 (10): 2899–908.
doi:
10.1021/bi982352c.
PMID10074342.
^J. Leban, D. Vitt, Human dihydroorotate dehydrogenase inhibitors, a novel approach for the treatment of autoimmune and inflammatory diseases, Arzneimittel-Forschung/Drug Res. (2011).
https://doi.org/10.1055/s-0031-1296169
^R.I. Christopherson, S.D. Lyons, P.K. Wilson, Inhibitors of de novo nucleotide biosynthesis as drugs, Acc. Chem. Res. (2002).
https://doi.org/10.1021/ar0000509
^M. Löffler, L.D. Fairbanks, E. Zameitat, A.M. Marinaki, H.A. Simmonds, Pyrimidine pathways in health and disease, Trends Mol. Med. (2005).
https://doi.org/10.1016/j.molmed.2005.07.003
^D. Lang, R. Thoma, M. Henn-Sax, R. Sterner, M. Wilmanns, Structural evidence for evolution of the β/α barrel scaffold by gene duplication and fusion, Science (80-. ). (2000).
https://doi.org/10.1126/science.289.5484.1546
^E. coli Dihydroorotate Dehydrogenase Reveals Structural and Functional Distinction between different classes of dihydroorotate dehydrogenases. DOI: 10.1016/s0969-2126(02)00831-6
^CRYSTAL STRUCTURE OF DIHYDROOROTATE DEHYDROGENSE from MYCOBACTERIUM TUBERCULOSIS. DOI: 10.2210/pdb4XQ6/pdb
^SAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti-Viral Activity. DOI: 10.1021/ml300464h
^Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors. DOI: 10.1021/jm500481t
^Structure of Plasmodium falciparum dihydroorotate dehydrogenase with a bound inhibitor. DOI: 10.1107/S0907444905042642