Catalyzes the first step of diphthamide biosynthesis, a post-translational modification of histidine which occurs in elongation factor 2 (PubMed:15485916, PubMed:24895408). 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:14744934, PubMed:15661533, PubMed:24895408). 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 (PubMed:15485916, PubMed:21203470). Interacts with RBM8A (By similarity). Punctate, primarily perinuclear localization. Strongly expressed in kidney and liver. Moderately expressed in brain, skin and testis. Weakly expressed in heart, lung, small intestine, spleen, stomach and thymus. Expressed in heart, neural tube, forebrain, mandible, tongue and body walls at 10.5 to 14.5 dpc (at protein level) (PubMed:24895408). Expressed in lung, stomach, brain, heart, kidney and gonads at 14.5 dpc (PubMed:11527402). Global developmental delay (PubMed:14744934, PubMed:24895408). Abnormal palatogenesis; palatine bone absent, micrognathia, cleft palate and small skull (PubMed:14744934, PubMed:24895408). Results in death during gestation or soon after birth with a small body size (PubMed:14744934). May also result in preaxial polydactyly of the right hindlimb and abnormal hepatic development (PubMed:14744934). Knockout mice leads to an increased frequency of tumor formation (PubMed:14744934, PubMed:24895408). Belongs to the DPH1/DPH2 family. DPH1 subfamily.