Mitochondrial peptide deformylase (PDF)

Mitochondrial peptide deformylase (PDF) is a nuclear-encoded metalloenzyme essential for the maturation of proteins synthesized within the mitochondria (UniProt Q9HBH1; NCBI Gene ID: 64146). In human mitochondria, as in bacteria, protein translation initiates with N-formylmethionine; PDF catalyzes the removal of this N-formyl group from nascent polypeptides, a step that is a prerequisite for subsequent N-terminal methionine excision (PMID: 15103325). This process is vital for the stability and assembly of the 13 proteins encoded by mitochondrial DNA, all of which are core subunits of the oxidative phosphorylation (OXPHOS) machinery (PMID: 20837555). Because many cancer cells rely heavily on mitochondrial biogenesis and OXPHOS to sustain rapid growth, PDF is often overexpressed in various malignancies, making it a promising target for anti-cancer therapy (PMID: 36812345). Inhibitors like the natural product actinonin can trigger mitochondrial proteotoxic stress and apoptosis in cancer cells by blocking this maturation process (PMID: 20837555). However, the high structural similarity between human mitochondrial PDF and bacterial PDF presents a therapeutic challenge, as antibacterial drugs targeting this enzyme must be carefully designed to avoid off-target mitochondrial toxicity in human patients (PMID: 22432445).

Other names

Peptide deformylase, mitochondrialPolypeptide deformylasePDFMPDFL1

Inhibition of the removal of the N-formyl group from the N-terminal methionine of nascent mitochondrial proteins, leading to impaired protein maturation, proteotoxic stress, and mitochondrial dysfunction.