Diphthamide biosynthesis protein 1 (DPH1)

Diphthamide biosynthesis protein 1 (DPH1) is an **iron–sulfur cluster enzyme** critical for the first step of diphthamide biosynthesis—a unique post-translational modification on a specific histidine residue (His715 in humans) of translation elongation factor 2 (EF2)[1][2]. This modification is essential for translational fidelity and is the direct target of bacterial toxins such as **diphtheria toxin** and **Pseudomonas exotoxin A**, which ADP-ribosylate diphthamide and thereby inhibit protein synthesis[1][2]. DPH1, together with DPH2 (and in coordination with DPH3 and DPH4 for electron transfer), catalyzes the transfer of a 3-amino-3-carboxypropyl group from S-adenosylmethionine to EF2, forming the key carbon–carbon bond required for diphthamide[1][2][3][5]. DPH1 is evolutionarily conserved across eukaryotes and archaea, and its function is linked to maintenance of translational accuracy and cellular stress responses, including regulation of TOR/mTOR signaling pathways that control growth and metabolism[4][5]. In humans, DPH1 also functions as a **tumor suppressor** (notably as OVCA1 in ovarian cancer), and loss-of-function mutations cause a congenital DPH1 deficiency syndrome with developmental abnormalities[2]. Due to its essential role in translation and cellular viability, **DPH1 is not a typical direct drug target**, but its loss or functionally altered variants have important biological and clinical implications. No approved drugs target DPH1 directly, but inhibitors of diphthamide synthesis or DPH1 function would broadly impact protein synthesis and cellular viability, representing a significant therapeutic challenge[2][3].

Other names

2-(3-amino-3-carboxypropyl)histidine synthase subunit 1DPH2LDPH2L1OVCA1DEDSSHDPH2-like 1OVCA1 (ovarian cancer-associated gene 1 protein)S-adenosyl-L-methionine:L-histidine 3-amino-3-carboxypropyltransferase 1diphtheria toxin resistance protein 1candidate tumor suppressor in ovarian cancer 1diphthamide biosynthesis protein 2 homolog-like 1

Drugs/toxins ADP-ribosylate diphthamide (on EF2, which requires DPH1 function for biosynthesis), thereby inhibiting protein synthesis