Catalyzes the first step of diphthamide biosynthesis, a post-translational modification of histidine which occurs in elongation factor 2 (PubMed:30877278). 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). Acts as a tumor suppressor (PubMed:10519411). L-histidyl-[translation elongation factor 2] + S-adenosyl-L-methionine = 2-[(3S)-amino-3-carboxypropyl]-L-histidyl-[translation elongation factor 2] + H(+) + S-methyl-5'-thioadenosine Binds 1 [4Fe-4S] cluster per subunit. The cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine. 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 DPH2 (By similarity). Interacts with RBM8A (PubMed:11013075). Punctate, primarily perinuclear localization. Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, mammary gland, colon, small intestine, testis and ovary. Reduced expression in primary breast and ovarian tumors. The disease is caused by variants affecting the gene represented in this entry. Belongs to the DPH1/DPH2 family. DPH1 subfamily. It is uncertain whether Met-1 or Met-6 is the initiator.