Required for the first step of diphthamide biosynthesis, a post-translational modification of histidine which occurs in elongation factor 2 (PubMed:32576952). DPH1 and DPH2 transfer a 3-amino-3-carboxypropyl (ACP) group from S-adenosyl-L-methionine (SAM) to a histidine residue, the reaction is assisted by a reduction system comprising DPH3 and a NADH-dependent reductase (By similarity). Facilitates the reduction of the catalytic iron-sulfur cluster found in the DPH1 subunit (By similarity).