Disease relevance of Actinonine

• Using the bacterium Salmonella enterica, we isolated mutants with resistance toward the peptide deformylase inhibitor actinonin [1].
• In the course of these experiments we demonstrated that treatment of Escherichia coli with the peptide deformylase inhibitor, actinonin, results in the expected (but previously unreported) accumulation of an N-formylated protein species [2].
• We investigated the antiproliferative effects of actinonin on human and murine leukemia and lymphoma cells [3].
• Here, we report the crystal structures of four bacterial deformylases, free or bound to the naturally occurring antibiotic actinonin, including two from the major bacterial pathogens Pseudomonas aeruginosa and Staphylococcus aureus [4].
• Exposure of several plant species including Arabidopsis to actinonin resulted in chlorosis and severe reductions in plant growth and development [5].

High impact information on Actinonine

• 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 [6].
• We show that actinonin, a peptidomimetic antibiotic that inhibits HsPDF, also inhibits the proliferation of 16 human cancer cell lines [6].
• 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 [6].
• Disruption of PDF1B in A.thaliana led to an albino phenotype, and an extreme sensitivity to the PDF- specific inhibitor actinonin [7].
• Actinonin, the most potent N-aminopeptidase inhibitor, was used to engage CD13 on sorted CD13(hi)Lin- cells and on culture day-7 bulk cells [8].

Chemical compound and disease context of Actinonine

• Among them, N-(2,6-diethylphenyl)homophthalimide (PIQ-22) possesses a specific aminopeptidase-inhibiting activity more potent than that of bestatin or actinonin, as assayed in terms of hydrolysis of L-alanine 4-methylcoumaryl-7-amide (Ala-AMC) by human acute lymphoblastic leukemia MOLT-4 cells [9].

Biological context of Actinonine

• All cycling cells appeared susceptible to actinonin, which induced cell apoptosis at the same time as Bcl-2 was downregulated and caspase-3 activity increased, but finally percentages and yields of DC and macrophage precursors were affected more than those of granulocytic cells [8].
• Peptide hydrolysis was inhibited by the metal-chelating agent 1,10-phenanthroline and by the aminopeptidase inhibitors actinonin, amastatin, and leuhistin [10].
• Actinonin inhibited growth of NB4 and HL60 human cell lines and AKR mouse leukemia cells in vitro with an IC50 of about 2-5 micrograms/ml [3].
• In addition, preincubation of MMP-2 and MMP-2deltaHP with the MMP inhibitor actinonin, which binds to the active site of MMP-2, abolished their bindings to endostatin [11].
• Probestin and another specific aminopeptidase inhibitor, actinonin, in addition to their capability of inducing erk-2 mRNA levels, significantly increase p42 phosphorylation state [12].

Anatomical context of Actinonine

• Actinonin, an antibiotic and CD13/aminopeptidase N (APN) inhibitor, has been shown to be cytotoxic to tumor cell lines in vitro [3].
• We tested this hypothesis by exposing Escherichia coli to subinhibitory doses of the PDF inhibitor actinonin and show that actinonin indeed increases the production and secretion of neutrophil-activating peptides that activate human neutrophils through FPR [13].
• In vivo, actinonin dose-dependently restored the stratum granulosum and ameliorated the impaired keratinocyte differentiation in the mouse tail model of psoriasis [14].
• Actinonin which has been found to be an inhibitor of aminopeptidase M (EC 3.4.11.2) also inhibited enkephalinase A (EC 3.4.24.11) and enkephalin aminopeptidase which were partially purified from the corpus striatum membrane of guinea-pig brain [15].
• Ubenimex and the more potent aminopeptidase inhibitor, actinonin, inhibited proliferation of both K562 cells and STI571-resistant K562 cells and also induced their apoptosis in dose- and time-dependent manners [16].

Associations of Actinonine with other chemical compounds

• Other cytosolic neutral aminopeptidase inhibitors such as actinonin and puromycin also augmented cell growth suppression by CH11, while an enantiomer of bestatin lacking aminopeptidase inhibitory action did not increase the growth-inhibitory effects of CH11 [17].
• Renal slices are protected from hypoxia-reoxygenation injury in vitro by the meprin inhibitor actinonin [18].
• Pre-treatment with the actinonin was markedly protective while not interfering with the hypoxia-induced fall in adenosine 5'-triphosphate (ATP) levels [18].
• To identify novel PDF inhibitors, we screened a metalloenzyme inhibitor library and identified an N-formyl-hydroxylamine derivative, BB-3497, and a related natural hydroxamic acid antibiotic, actinonin, as potent and selective inhibitors of PDF [19].
• This induction-dependent increase of GSK-3beta is markedly reduced in response to inhibitors of alanyl-aminopeptidase, actinonin, leuhistin, and RB3014 [20].

Gene context of Actinonine

• A structurally different aminopeptidase N inhibitor, actinonin, also increased the effect of ATRA on differentiation, but an inactive stereoisomer of bestatin, (2R,3S)-AHPA-(R)-Leu, did not [21].
• We have identified actinonin, a naturally occurring antibacterial agent, as a potent PDF inhibitor [22].
• Susceptibility to actinonin was restored when the wild-type fmt gene was introduced into these mutant strains [23].
• Mechanism of time-dependent inhibition of polypeptide deformylase by actinonin [24].
• The mode of antibacterial action of actinonin, a known PDF inhibitor, was also confirmed with this strain [25].

Analytical, diagnostic and therapeutic context of Actinonine

• Cell cycle analysis showed that actinonin induces a G1 arrest in HL60 and NB4 cells; apoptosis was observed in 20-35% of the cells as measured by intracellular flow cytometry [3].
• Subinhibitory concentrations of the deformylase inhibitor actinonin increase bacterial release of neutrophil-activating peptides: a new approach to antimicrobial chemotherapy [13].
• In in vivo studies, rats exposed to ischemia/reperfusion injury were markedly protected against acute renal failure by IP treatment with actinonin [18].
• Sequence analysis of the actinonin-resistant mutants revealed that each harbors a loss-of-function mutation in the fmt gene [23].
• Actinonin was found to inhibit all three enzymes of enkephalin metabolism and, when given peripherally, to potentiate enkephalin analgesia [15].

References