Emerging concepts in the flavinylation of succinate dehydrogenase

The Succinate Dehydrogenase (SDH) heterotetrameric complex catalyzes the oxidation of succinate to fumarate in the tricarboxylic acid (TCA) cycle and in the aerobic respiratory chains of eukaryotes and bacteria. Essential in this catalysis is the covalently-linked cofactor flavin adenine dinucleotide (FAD) in subunit1 (Sdh1) of the SDH enzyme complex. The mechanism of FAD insertion and covalent attachment to Sdh1 is unknown. Our working concept of this flavinylation process has relied mostly on foundational works from the 1990s and by applying the principles learned from other enzymes containing a similarly linked FAD. The discovery of the flavinylation factor Sdh5, however, has provided new insight into the possible mechanism associated with Sdh1 flavinylation. This review focuses on encapsulating prior and recent advances towards understanding the mechanism associated with flavinylation of Sdh1 and how this flavinylation process affects the overall assembly of SDH. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.

► The mechanism of FAD covalent attachment to Sdh1 has been a long-standing question.
► The discovery of Sdh5 suggests that Sdh1 flavinylation is a complex, non-autocatalytic process.
► FAD and succinate binding to Sdh1 and its binding to Sdh5 and Sdh2 are important in flavinylation.
► A conceptual model is presented based on prior/current findings in flavinylation/SDH assembly.