Dihydroorotate dehydrogenase (quinone) explained

Dihydroorotate:quinone oxidoreductase
Symbol:	DHOQO
Ec Number:	1.3.5.2
Cas Number:	59088-23-2

Class 2 dihydroorotate dehydrogenases (DHOQO,) is an enzyme with systematic name (S)-dihydroorotate:quinone oxidoreductase.^{[1] [2] [3] [4] [5]} This enzyme catalyses the electron transfer from dihydroorotate (electron donor) to a quinone (electron acceptor):

\rightleftharpoons orotate + quinol

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

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:

• Escherichia coli (example PDB:1F76)^[10]
• Mycobacterium tuberculosis (example PDB: 4XQ6)^[11]
• Homo sapiens (example PDB:4IGH)^[12]
• Rattus norvegicus (example PDB: 4ORI)^[13]
• Plasmodium falciparum (example PDB: 1TV5)^[14]

Notes and References

1. Forman HJ, Kennedy J . Mammalian dihydroorotate dehydrogenase: physical and catalytic properties of the primary enzyme . Archives of Biochemistry and Biophysics . 191 . 1 . 23–31 . November 1978 . 216313 . 10.1016/0003-9861(78)90063-2 .
2. Hines V, Keys LD, Johnston M . Purification and properties of the bovine liver mitochondrial dihydroorotate dehydrogenase . The Journal of Biological Chemistry . 261 . 24 . 11386–92 . August 1986 . 10.1016/S0021-9258(18)67396-X . 3733756 . free .
3. Bader B, Knecht W, Fries M, Löffler M . Expression, purification, and characterization of histidine-tagged rat and human flavoenzyme dihydroorotate dehydrogenase . Protein Expression and Purification . 13 . 3 . 414–22 . August 1998 . 9693067 . 10.1006/prep.1998.0925 .
4. Fagan RL, Nelson MN, Pagano PM, Palfey BA . Mechanism of flavin reduction in class 2 dihydroorotate dehydrogenases . Biochemistry . 45 . 50 . 14926–32 . December 2006 . 17154530 . 10.1021/bi060919g .
5. Björnberg O, Grüner AC, Roepstorff P, Jensen KF . 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 . March 1999 . 10074342 . 10.1021/bi982352c .
6. 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
7. 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
8. 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
9. 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
10. E. coli Dihydroorotate Dehydrogenase Reveals Structural and Functional Distinction between different classes of dihydroorotate dehydrogenases. DOI: 10.1016/s0969-2126(02)00831-6
11. CRYSTAL STRUCTURE OF DIHYDROOROTATE DEHYDROGENSE from MYCOBACTERIUM TUBERCULOSIS. DOI: 10.2210/pdb4XQ6/pdb
12. SAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti-Viral Activity. DOI: 10.1021/ml300464h
13. Fluorine Modulates Species Selectivity in the Triazolopyrimidine Class of Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors. DOI: 10.1021/jm500481t
14. Structure of Plasmodium falciparum dihydroorotate dehydrogenase with a bound inhibitor. DOI: 10.1107/S0907444905042642