Diphthamide, the target of diphtheria toxin, is a post-translationally modified histidine residue found in eukaryotic translation elongation factor 2 (EF2). The Dph1-Dph2 heterodimer acts in the first step of diphthamide biosynthesis by cleaving S-adenosylmethionine and transferring the 3-amino-3-carboxypropyl group to EF2. The [4Fe-4S] cluster-binding cysteine residues in each subunit are required for diphthamide biosynthesis - the Dph1 cluster is thought to serve a catalytic role, while the Dph2 cluster facilitates the reduction of the Dph1 cluster. (Adapted from
PMID:31463593.)
