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). Binds 1 [4Fe-4S] cluster per subunit. The cluster facilitates the reduction of the catalytic iron-sulfur cluster in the DPH1 subunit. Protein modification; peptidyl-diphthamide biosynthesis. Component of the 2-(3-amino-3-carboxypropyl)histidine synthase complex composed of DPH1, DPH2, DPH3 and a NADH-dependent reductase (By similarity). Interacts with DPH1 (By similarity). Strongly expressed in skeletal muscle. Moderately expressed in heart, small intestine, liver, pancreas, testis and colon. Weakly expressed in brain, placenta, kidney, spleen, thymus, prostate, ovary and lymphocytes. Defects in DPH2 may be the cause of diphthamide-deficiency syndrome (PubMed:32576952). Affected individuals may present with infantile macrocephaly, developmental delay, short stature, dysmorphic craniofacial features, and congenital heart disease (PubMed:32576952). Belongs to the DPH1/DPH2 family. DPH2 subfamily.