![]() There are 3 classes of PDFs based on structural and sequence analyses ( 16, 17). Nyu macvector pdf#While PDF was originally thought to be a prokaryotic enzyme, recent genome-database searches have revealed eukaryotic PDF-like sequences in parasites, plants, and mammals ( 10), and recent studies have shown that these eukaryotic PDFs are active in vitro and in vivo ( 11– 15). The development of antimicrobial agents targeting PDF could encounter a potential hurdle. In fact, numerous PDF inhibitors have been shown to have in vitro activities against several of these pathogens, and it has been speculated that these same molecules could be used as broad-spectrum antibiotics against a variety of infectious diseases ( 9). These include Thermus thermophilus and Bacillus stearothermophilus ( 4), Staphylococcus aureus ( 5), Haemophilus influenzae, Streptococcus pneumoniae ( 6), Leptospira interrogans ( 7), and Mycobacterium tuberculosis ( 8). coli, there is an increasing interest in PDF as a target for developing therapies against other pathogens. PDF removes all N-formyl groups and unmasks the amino group of the first methionine, which is a prerequisite for the subsequent action of MAP ( 2).Īlthough most of the initial work characterizing PDFs has focused on E. Two enzyme families are involved in this NME pathway, peptide deformylase (PDF) and methionine aminopeptidase (MAP). Although N-formyl groups modify the first methionine of all newly synthesized proteins in the cytoplasm of prokaryotes and organelles of eukaryotes, this formyl-methionine is often not retained and is cleaved from the mature protein as a part of a posttranslational modification that may be linked to the N-end rule governing the half-lives of proteins ( 3). The N-terminal methionine excision (NME) pathway is an essential mechanism in all organisms ( 1, 2). We conclude that HsPDF is a new human mitochondrial enzyme that may provide a novel selective target for anticancer therapy by use of actinonin-based antibiotics. In animal models, oral or parenteral actinonin was well tolerated and inhibited human prostate cancer and lung cancer growth. Actinonin treatment of cells led to a tumor-specific mitochondrial membrane depolarization and ATP depletion in a time- and dose-dependent manner removal of actinonin led to a recovery of the membrane potential consistent with indirect effects on the electron transport chain. Small interfering RNA inhibition of HsPDF protein expression was also antiproliferative. We designed and synthesized 33 chemical analogs of actinonin all of the molecules with potent activity against HsPDF also inhibited tumor cell growth, and vice versa, confirming target specificity. We show that actinonin, a peptidomimetic antibiotic that inhibits HsPDF, also inhibits the proliferation of 16 human cancer cell lines. HsPDF is capable of removing formyl groups from N-terminal methionines of newly synthesized mitochondrial proteins, an activity previously not thought to be necessary in mammalian cells. We describe here a new human peptide deformylase ( Homo sapiens PDF, or HsPDF) that is localized to the mitochondria. Collectively, these data indicate that PEL originate from mature, antigen-experienced B cells and bear implications for the pathogenesis and histogenesis of this lymphoma.Peptide deformylase activity was thought to be limited to ribosomal protein synthesis in prokaryotes, where new peptides are initiated with an N-formylated methionine. Evidence for selection was more frequent in the light chain genes than in the heavy chain genes. Statistical evidence for antigen selection was evident in four out of seven samples studied. In all cases, significant deviations from the presumed germline counterpart were found in both the expressed V H and V L genes. Two cases expressed μ chains, whereas γ chains were found in two cases. Most of the samples (five out of seven) used lambda light chain genes the majority of these ( n = 4) belonged to the V lambda 3 family. ![]() In order to assess the specific variable heavy (V H) and light (V L) genes used by PEL and to define the heavy and light chain isotypes expressed by these lymphomas, immunoglobulin (Ig) genes from seven AIDS-related PEL were sequenced (three cell lines and four primary samples). ![]() ![]() ![]() The aim of the present study was to investigate the role of antigen stimulation and selection in the evolution of PEL. Apart from viral infection, the pathogenesis of PEL is currently unclear. Primary effusion lymphoma (PEL) is a lymphoproliferation of B cells infected by Kaposi’s sarcoma-associated herpes- virus/human herpesvirus-8 and reflecting a late stage of B cell differentiation close to plasma cell. ![]()
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