Flavin-containing cofactors play an important role in many enzymatic biochemical reactions that involve electron and/or group transfer. In some, but not all flavin-containing enzymes, the cofactor is covalently bound. This is not a trivial distinction, because covalent binding alters the redox potential of the flavin, a change frequently required to enable the cofactor to carry out its intended chemical reaction. Despite the importance of covalent flavinylation of some enzymes, the mechanism by which this process is occurs is poorly understood. To address this question, Vanderbilt Basic Sciences investigator Tina Iverson, her collaborator Gary Cecchini (UCLA), and their laboratories have been investigating the structure of the quinol:fumarate reductase A (FrdA) subunit of respiratory complex II from E. coli. FrdA, which catalyzes the interconversion of succinate and fumarate, contains a covalently bound FAD cofactor in its active site. Past studies had suggested that formation of that covalent FAD-protein bond might be autocatalytic, might be promoted by the presence of dicarboxylic acids, and/or might be facilitated by an assembly factor, SdhE. The Iverson and Cecchini labs determined the crystal structure of a stable FrdA/SdhE assembly. The details of this structure show that binding of FrdA to SdhE stabilizes a conformation of SdhE that disfavors the succinate/fumarate interconversion reaction and favors the formation of the covalent bond between a histidine residue of the protein and FAD. The findings provide a structural foundation for a flavinylation mechanism that also accounts for all prior observations of the process. The work is published in the journal Nature Communications [P. Sharma, et al. Nat. Commun., (2018) 9, 274].
Figure reproduced under the Creative Commons Attribution 4.0 International License 4.0 from P. Sharma, et al. Nat. Commun., (2018) 9, 274.