Required for the first step of diphthamide biosynthesis, a post-translational modification of histidine which occurs in elongation factor 2 (PubMed:15485916, PubMed:18627462, PubMed:24422557, PubMed:27694803, PubMed:31463593, PubMed:34154323, PubMed:25543256). 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 KTI11/DPH3 and a NADH-dependent reductase, predominantly CBR1 (PubMed:24422557, PubMed:27694803, PubMed:31463593, PubMed:34154323). Acts as an electron donor to reduce the Fe-S cluster in DPH1-DPH2 keeping the [4Fe-4S] clusters in the active and reduced state (PubMed:34154323). Restores iron to DPH1-DPH2 iron-sulfur clusters which have degraded from [4Fe-4S] to [3Fe-4S] by donating an iron atom to reform [4Fe-4S] clusters, in a manner dependent on the presence of elongation factor 2 and SAM (PubMed:34154323). Together with ATS1; associates with the elongator complex and is required for tRNA Wobble base modifications mediated by the elongator complex (PubMed:25543256, PubMed:27694803, PubMed:18627462). The elongator complex is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s 2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine) (PubMed:25543256). [3Fe-4S](1+)-[protein] + Fe(2+)-[Dph3] = [3Fe-4S](0)-[protein] + Fe(3+)-[Dph3] 2 [3Fe-4S](0)-[protein] + 2 Fe(2+)-[Dph3] + NADH = 2 [4Fe-4S](1+)-[protein] + 2 [Dph3] + H(+) + NAD(+) Protein modification; peptidyl-diphthamide biosynthesis. Component of the 2-(3-amino-3-carboxypropyl)histidine synthase complex composed of DPH1, DPH2, KTI11/DPH3 and a NADH-dependent reductase, predominantly CBR1 (PubMed:12940988, PubMed:27694803, PubMed:18627462, PubMed:23645155). Interacts with DPH1 (PubMed:12940988, PubMed:27694803, PubMed:18627462, PubMed:23645155). Interacts with DPH2 (PubMed:12940988, PubMed:27694803, PubMed:18627462). Interacts with CBR1 (PubMed:27694803). Interacts with elongation factor 2 (PubMed:12940988). Interacts with ATS1/KTI13; the interaction is direct (PubMed:25604895, PubMed:25543256, PubMed:18627462). Interacts with the 40S ribosomal protein RPS7A (PubMed:12940988). Interacts with the 40S ribosomal protein RPS19A (PubMed:12940988). Interacts with the elongator complex subunit IKI3/ELP1 (PubMed:12940988, PubMed:18986986, PubMed:27694803). Interacts with the elongator complex subunit ELP2 (PubMed:12940988, PubMed:18986986, PubMed:27694803, PubMed:18627462). Interacts with the elongator complex subunit ELP3 (PubMed:12940988, PubMed:18986986, PubMed:27694803). Interacts with the elongator complex subunit ELP5 (PubMed:18627462). The DPH-type metal-binding (MB) domain can also bind zinc. However, iron is the physiological binding partner as zinc binding impairs the protein electron donor function. Sensitive to caffeine, paromycin, and thermal stress (PubMed:18627462). Resistance to diphtheria toxin, sordarin and zymocin (PubMed:27694803, PubMed:18627462). Present with 8400 molecules/cell in log phase SD medium. Belongs to the DPH3 family.