E. coli Dihydroorotate Dehydrogenase Reveals Structural and Functional Distinctions between Different Classes of Dihydroorotate Dehydrogenases

• Published in: Structure (London) Vol. 10; no. 9; pp. 1211 - 1223
• Main Authors: Nørager, Sofie, Jensen, Kaj Frank, Björnberg, Olof, Larsen, Sine
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2002
• Subjects: Amino Acid Sequence; Binding Sites; Crystallography, X-Ray; Escherichia coli - enzymology; flavoproteins; Humans; hydride transfer; Hydrogen Bonding; Models, Molecular; orotate binding; Oxidoreductases - chemistry; Oxidoreductases - classification; Oxidoreductases - metabolism; Oxidoreductases Acting on CH-CH Group Donors; Protein Binding; Protein Conformation; Protein Folding; pyrimidine nucleotide biosynthesis; reaction mechanism; Sequence Homology, Amino Acid; structural comparisons; Structure-Activity Relationship; orotate binding; structural comparisons; reaction mechanism; hydride transfer; flavoproteins; pyrimidine nucleotide biosynthesis
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/S0969-2126(02)00831-6

The flavoenzymes dihydroorotate dehydrogenases (DHODs) catalyze the fourth and only redox step in the de novo biosynthesis of UMP. Enzymes belonging to class 2, according to their amino acid sequence, are characterized by having a serine residue as the catalytic base and a longer N terminus. The structure of class 2 E. coli DHOD, determined by MAD phasing, showed that the N-terminal extension forms a separate domain. The catalytic serine residue has an environment differing from the equivalent cysteine in class 1 DHODs. Significant differences between the two classes of DHODs were identified by comparison of the E. coli DHOD with the other known DHOD structures, and differences with the class 2 human DHOD explain the variation in their inhibitors.