Diphthamide biosynthesis protein 2 (DPH2)

Diphthamide biosynthesis protein 2 (DPH2) is an enzyme critical for the first step in the biosynthesis of diphthamide, a unique post-translational modification found exclusively at a conserved histidine residue of eukaryotic elongation factor 2 (eEF2). DPH2, as part of a heterodimeric enzyme complex with DPH1, transfers a 3-amino-3-carboxypropyl (ACP) group from S-adenosylmethionine to eEF2. This modification is essential for maintaining translational fidelity and reading frame maintenance during protein synthesis. The diphthamide residue on eEF2 is the unique target of bacterial ADP-ribosylating toxins such as diphtheria toxin, and absence of a functional DPH2 pathway confers resistance to these toxins but leads to impaired translation accuracy and, in multicellular organisms, can result in developmental defects or embryonic lethality. The DPH2 protein belongs to the radical SAM enzyme family and is highly conserved among archaea and eukaryotes due to its fundamental role in core translational mechanisms[1][2][3].

Other names

2-(3-amino-3-carboxypropyl)histidine synthase subunit 2DPH2L2DEDSSH2Diphtheria toxin resistance protein 2S-adenosyl-L-methionine:L-histidine 3-amino-3-carboxypropyltransferase 2Diphthamide biosynthesis-like protein 2Diphthamide biosynthesis protein 2 homolog-like 2

Drugs like diphtheria toxin inactivate elongation factor 2 by ADP-ribosylating the diphthamide residue, whose biosynthesis requires DPH2[1][2]. Sordarin sensitivity depends on presence of diphthamide on EF2[3].