Dicyclohexylamine, a potent inhibitor of spermidine synthase in mammalian cells

Hibasami, Hiroshige; Tanaka, Minoru; Nagai, Jun; Ikeda, Takako

doi:10.1016/0014-5793(80)80537-0

Cited by 88 publications

(27 citation statements)

References 15 publications

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“…Bacteria can either make their own polyamines (putrescine and spermidine) or import polyamines (spermidine, putrescine, and spermine) from the extracellular environment to grow (64). To identify mutants that were unable to utilize extracellular polyamines, we used an inhibitor of spermidine synthase, dicyclohexylamine (3,9,27,37,43). Isolates were selected from a library of mutants made with a Mariner-based transposon (50) that were unable to replicate in the presence of both the inhibitor and spermine in CDM.…”

Section: Resultsmentioning

confidence: 99%

A Francisella tularensis Locus Required for Spermine Responsiveness Is Necessary for Virulence

et al. 2011

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Tularemia is a debilitating febrile illness caused by the category A biodefense agent Francisella tularensis. This pathogen infects over 250 different hosts, has a low infectious dose, and causes high morbidity and mortality. Our understanding of the mechanisms by which F. tularensis senses and adapts to host environments is incomplete. Polyamines, including spermine, regulate the interactions of F. tularensis with host cells. However, it is not known whether responsiveness to polyamines is necessary for the virulence of the organism. Through transposon mutagenesis of F. tularensis subsp. holarctica live vaccine strain (LVS), we identified FTL_0883 as a gene important for spermine responsiveness. In-frame deletion mutants of FTL_0883 and FTT_0615c, the homologue of FTL_0883 in F. tularensis subsp. tularensis Schu S4 (Schu S4), elicited higher levels of cytokines from human and murine macrophages compared to wild-type strains. Although deletion of FTL_0883 attenuated LVS replication within macrophages in vitro, the Schu S4 mutant with a deletion in FTT_0615c replicated similarly to wild-type Schu S4. Nevertheless, both the LVS and the Schu S4 mutants were significantly attenuated in vivo. Growth and dissemination of the Schu S4 mutant was severely reduced in the murine model of pneumonic tularemia. This attenuation depended on host responses to elevated levels of proinflammatory cytokines. These data associate responsiveness to polyamines with tularemia pathogenesis and define FTL_0883/FTT_0615c as an F. tularensis gene important for virulence and evasion of the host immune response.

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Section: Resultsmentioning

confidence: 99%

A Francisella tularensis Locus Required for Spermine Responsiveness Is Necessary for Virulence

et al. 2011

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“…However, copious putrescine accumulation occurred with MGBG and DCHA additions (up to one-half of the putrescine made was excreted into the medium). MGBG inhibits S-adenosylmethionine decarboxylase (18), and DCHA inhibits spermidine synthase (19) in most organisms tested. The effects of these compounds upon the polyamine pools of N. crassa (Table 1) are consistent with these modes of action, although their specificities cannot be taken for granted.…”

Section: Resultsmentioning

confidence: 99%

Distinct roles of putrescine and spermidine in the regulation of ornithine decarboxylase in Neurospora crassa.

Davis¹,

Krasner²,

DiGangi³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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We wished to identify metabolic signals governing changes in ornithine decarboxylase (L-ornithine carboxy-lyase, EC 4.1.1.17) activity in Neurospora crassa. By manipulations of the ornithine supply and by the use of inhibitors of the polyamine pathway, we found that spermidine negatively governs formation of active ornithine decarboxylase and that putrescine promotes inactivation of the enzyme. Direct addition of putrescine or spermidine to cycloheximide-treated cells confirmed the role of putrescine in enzyme inactivation and showed that spermidine had no effect on this process. Increases in ornithine decarboxylase activity caused by blocking spermidine synthesis occurred prior to a significant decrease in the spermidine pool. This is consistent with our prevous finding that only 10-20% of the spermidine pool is freely diffusible within N. crassa cells. We presume that only this small fraction of the pool is active in regulation.Ornithine decarboxylase (OrnDCase; L-ornithine carboxylyase, EC 4.1.1.17) is a key enzyme of the synthesis of polyamines (putrescine, spermidine, and spermine) in most fungi and animals (1-3). While the roles of polyamines in vivo are still uncertain, these compounds are indispensable in eukaryotes (2). An increase of OrnDCase activity and an increased rate of polyamine synthesis are correlated with the onset of rapid growth, of transformation to the neoplastic state, and of periods of cell differentiation in most organisms (see refs. in ref. 2). Moreover, OrnDCase is rapidly inactivated upon the cessation of growth or upon addition of polyamines to cells. The regulation of the amount of active enzyme is the major mechanism of control; feedback and product inhibition are weak or absent.A test of polyamine pathway intermediates ( Fig. 1) for their roles in regulating the OrnDCase of Neurospora crassa is reported here. We identify spermidine and putrescine as regulatory signals governing, respectively, the formation and inactivation of OrnDCase catalytic activity. The work is discussed in connection with our previous observations (4-6) that polyamines are highly compartmentalized in cells of N.crassa. MATERIALS AND METHODSStrains, Growth, and Sampling. The strain of N. crassa used was IC3, a prototrophic strain carrying the arginase-less (aga) allele, UM-906. Vogel's medium N (7) was used for growth. Cultures were grown exponentially in 1-liter aerated cultures (8) for determinations of growth rate, enzyme activity, and polyamine pools. Samples (20 ml) for dry weight were collected on Whatman no. 1 filter circles and dried with acetone. Mycelial samples (10 ml) for polyamine determinations were collected and washed on membrane filters (pore size, 5 ,um). The pad was extracted with 1 ml of 0.4 M perchloric acid with 1 mM EDTA. As an internal standard, 100 nmol of 1,7-diaminoheptane was added before centrifugation; the supernatant was saved and frozen until use. Mycelial samples (5 ml) for enzyme assay were permeabilized with a toluene/ethanol solution, followed by freezing (9).OrnD...

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“…A number of investigators have used inhibitors of PA to modulate the cellular PAs level in order to determine their role in various plant processes. Most widely used inhibitors of various enzymes of PA biosynthesis and catabolism are difluoromethylornithine (DFMO), an irreversible inhibitor of ODC ; difluoromethylarginine (DFMA), an irreversible inhibitor of ADC (Bitonti et al 1987); methylglyoxalbisguanylhydrazine (MGBG), a competitive inhibitor of SAMDC (Williams-Ashman & Schenone 1972); CHA, a competitive inhibitor of SPDS (Hibasami et al 1980); aminoguanidine (AG) for DAO and others. Treatment with biosynthetic inhibitors of PA reduced stress tolerance but this effect is reversed by concomitant application of exogenous PAs (He et al 2002).…”

Section: Use Of Inhibitors and Stress Responsementioning

confidence: 99%

Polyamines: potent modulators of plant responses to stress

Fariduddin

Varshney

Yusuf

et al. 2013

Journal of Plant Interactions

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Polyamines (PAs) are aliphatic polycations that are widespread in living organisms. In this review, we are focusing the correlation between endogenous PA titers and physiological perturbations and on the protective role of various analogues of PAs against abiotic stresses. PAs are involved in many physiological processes, such as cell growth and development and also respond to diverse abiotic stresses. Polyamines level shifts in different ways depending on several factors, such as plant species, tolerance or sensitivity to stress, and duration of stress. Exogenously supplied PAs protected plants from abiotic stress, whereas transgenic plants overexpressing PA biosynthetic genes exhibited stress tolerance. On the other hand, loss-of-function mutant of PA biosynthetic genes, or decrease of PA titers, resulted to decrease stress tolerance.

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Dicyclohexylamine, a potent inhibitor of spermidine synthase in mammalian cells

Cited by 88 publications

References 15 publications

A Francisella tularensis Locus Required for Spermine Responsiveness Is Necessary for Virulence

A Francisella tularensis Locus Required for Spermine Responsiveness Is Necessary for Virulence

Distinct roles of putrescine and spermidine in the regulation of ornithine decarboxylase in Neurospora crassa.

Polyamines: potent modulators of plant responses to stress

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