Human Diphthamide Biosynthesis Protein 2 (DPH2) Protein

Background

DPH2 is an essential enzyme that works in concert with DPH1 to catalyze the first step of diphthamide biosynthesis on eukaryotic elongation factor 2 (eEF2), forming a critical intermediate for subsequent modifications. It interacts directly with DPH1 to mediate the transfer of a 3-amino-3-carboxypropyl group from S-adenosylmethionine (SAM) to the imidazole ring of a specific histidine residue. DPH2 mutations are associated with defects in protein translation fidelity and resistance to diphtheria toxin, as this toxin specifically targets diphthamide. Structural studies of DPH2 reveal conserved binding sites for SAM, emphasizing its central role in catalytic function. In addition to its enzymatic role, DPH2 is required for maintaining normal cellular physiology, particularly in protein synthesis and stress responses. DPH2 expression is tightly regulated and primarily localized in the cytoplasm, where it coordinates with other diphthamide biosynthesis factors. Deficiencies in DPH2 activity result in incomplete diphthamide synthesis, impacting cellular growth and proliferation. Its evolutionary conservation highlights its critical role in cellular and organismal viability.