{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHuman peptide deformylase (PDF) is a mitochondrial enzyme that catalyzes the removal of the N‐formyl group from the initiating methionine of nascent peptides—a key step in the N-terminal methionine excision pathway. Studies have demonstrated that the human PDF (HsPDF) exhibits deformylase activity, though at a slower rate and lower catalytic efficiency compared to its bacterial and plant counterparts. Biochemical characterization further revealed that HsPDF requires specific metal cofactors (with cobalt being particularly effective) and operates optimally over a physiological range of pH and temperature. Structural analyses have shown that HsPDF maintains a conserved catalytic core with a distinct substrate-binding pocket that accommodates formylated peptides deriving from mitochondrial DNA‐encoded proteins."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its fundamental role in mitochondrial protein maturation, HsPDF has emerged as a promising therapeutic target in oncology. Inhibition of HsPDF—for instance, by the peptidomimetic antibiotic actinonin or newly designed small molecules identified via high-throughput virtual screening—disrupts mitochondrial translation, depolarizes the mitochondrial membrane, and triggers apoptotic cell death preferentially in cancer cells that overexpress HsPDF. These findings underscore the enzyme’s potential utility in anticancer strategies, with ongoing investigations also aimed at detailing its expression patterns in human tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the genomic level, the regulation of the HsPDF gene is further complicated by its unusual overlap with the COG8 gene. Detailed promoter analyses have revealed that HsPDF is transcribed from multiple start sites, with a minimal promoter element—harboring conserved Sp1 binding sites—located immediately downstream of the COG8 coding region. Evolutionary studies suggest that this overlapping gene arrangement emerged through the acquisition of novel splice sites and loss of ancestral polyadenylation signals, ensuring that HsPDF is regulated independently despite its intimate genomic proximity to COG8."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mona D Lee, Christophe Antczak, Yueming Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A new human peptide deformylase inhibitable by actinonin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2003.10.123"}], "href": "https://doi.org/10.1016/j.bbrc.2003.10.123"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14637138"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14637138"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Sindy Escobar-Alvarez, Yehuda Goldgur, Guangli Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure and activity of human mitochondrial peptide deformylase, a novel cancer target."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2009.02.032"}], "href": "https://doi.org/10.1016/j.jmb.2009.02.032"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19236878"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19236878"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Harsharan Randhawa, Shireen Chikara, Drew Gehring, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of peptide deformylase in breast, colon, and lung cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Cancer (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2407-13-321"}], "href": "https://doi.org/10.1186/1471-2407-13-321"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23815882"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23815882"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "A Sheth, S Escobar-Alvarez, J Gardner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of human mitochondrial peptide deformylase causes apoptosis in c-myc-overexpressing hematopoietic cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cddis.2014.112"}], "href": "https://doi.org/10.1038/cddis.2014.112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24675470"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24675470"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jian Gao, Tao Wang, Shengzhi Qiu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure-Based Drug Design of Small Molecule Peptide Deformylase Inhibitors to Treat Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Molecules (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/molecules21040396"}], "href": "https://doi.org/10.3390/molecules21040396"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27023495"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27023495"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Isabel Pereira-Castro, Luís Teixeira da Costa, António Amorim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptional regulation of the human mitochondrial peptide deformylase (PDF)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2012.04.097"}], "href": "https://doi.org/10.1016/j.bbrc.2012.04.097"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22554513"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22554513"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Isabel Pereira-Castro, Rita Quental, Luís T da Costa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Successful COG8 and PDF overlap is mediated by alterations in splicing and polyadenylation signals."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-011-1075-9"}], "href": "https://doi.org/10.1007/s00439-011-1075-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21805148"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21805148"}]}]}]}