1-Aminooxy-3-aminopropane, a new and potent inhibitor of polyamine biosynthesis that inhibits ornithine decarboxylase, adenosylmethionine decarboxylase and spermidine synthase

Khomutov, R. M.; Hyvönen, Tapani; Karvonen, Eira; Kauppinen, Leila; Paalanen, T.; Paulín, Lars; Eloranta, Terho O.; Pajula, Raija-Leena; Andersson, LC; Pösö, Hannu

doi:10.1016/0006-291x(85)90458-9

Cited by 43 publications

(16 citation statements)

References 34 publications

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“…However, since mice infected with spermidine synthase mutants remained healthy throughout the course of the experiment, spermidine synthase may be a more useful anticryptococcal, and perhaps antifungal, drug target. At least four spermidine synthase inhibitors have been developed (2,20,22,34), at least one of which (cyclohexylamine) is known to inhibit C. neoformans growth (36). The transcription of S. cerevisiae LYS9 is regulated in response to lysine levels.…”

Section: Discussionmentioning

confidence: 99%

Novel Chimeric Spermidine Synthase-Saccharopine Dehydrogenase Gene ( SPE3-LYS9 ) in the Human Pathogen Cryptococcus neoformans

Kingsbury¹,

Yang²,

Ganous³

et al. 2004

Eukaryot Cell

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The Cryptococcus neoformans LYS9 gene (encoding saccharopine dehydrogenase) was cloned and found to be part of an evolutionarily conserved chimera with SPE3 (encoding spermidine synthase). spe3-lys9, spe3-LYS9, and SPE3-lys9 mutants were constructed, and these were auxotrophic for lysine and spermidine, spermidine, and lysine, respectively. Thus, SPE3-LYS9 encodes functional spermidine synthase and saccharopine dehydrogenase gene products. In contrast to Saccharomyces cerevisiae spe3 mutants, the polyamine auxotrophy of C. neoformans spe3-LYS9 mutants was not satisfied by spermine. In vitro phenotypes of spe3-LYS9 mutants included reduced capsule and melanin production and growth rate, while SPE3-lys9 mutants grew slowly at 30°C, were temperature sensitive in rich medium, and died upon lysine starvation. Consistent with the importance of saccharopine dehydrogenase and spermidine synthase in vitro, spe3-lys9 mutants were avirulent and unable to survive in vivo and both functions individually contributed to virulence. SPE3-LYS9 mRNA levels showed little evidence of being influenced by exogenous spermidine or lysine or starvation for spermidine or lysine; thus, any regulation is likely to be posttranscriptional. Expression in S. cerevisiae of the full-length C. neoformans SPE3-LYS9 cDNA complemented a lys9 mutant but not a spe3 mutant. However, expression in S. cerevisiae of a truncated gene product, consisting of only C. neoformans SPE3, complemented a spe3 mutant, suggesting possible modes of regulation. Therefore, we identified and describe a novel chimeric SPE3-LYS9 gene, which may link spermidine and lysine biosynthesis in C. neoformans.

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Section: Discussionmentioning

confidence: 99%

Novel Chimeric Spermidine Synthase-Saccharopine Dehydrogenase Gene ( SPE3-LYS9 ) in the Human Pathogen Cryptococcus neoformans

Kingsbury¹,

Yang²,

Ganous³

et al. 2004

Eukaryot Cell

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“…Since this parasite enzyme has a lower turnover rate, when compared to mammalian homologs [42,66], treatment of experimental leishmaniasis with ODC inhibitors, such as D, L-α-difluoromethylornithine (DFMO) [67] and 3-aminooxy-1-aminopropane (APA) [68][69][70], is an effective measure for controlling parasitic infection [42,71]. In addition to the enzymes in Larginine metabolic pathways, the L-arginine transporter may serve as a potential target for antileishmania drugs.…”

Section: Targeting L-arginine Metabolic Pathways As a Therapeutic Appmentioning

confidence: 99%

L-arginine metabolism and its impact on host immunity against Leishmania infection

2007

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Leishmaniasis is a vector-borne disease found in many countries worldwide. The causative agent of the disease, Leishmania spp., lives as an obligate intracellular parasite within mammalian hosts. Since tissue macrophages are major target cells for parasite replication, the outcome of infection depends largely on the activation status of these cells. L-arginine is a crucial amino acid required for both nitric oxide (NO)-mediated parasite killing and polyamine-mediated parasite replication. This review highlights the significance of L-arginine as a factor determining the outcomes of Leishmania infection in vitro and its influences on host immune responses in vivo. Various therapeutic approaches targeting L-arginine metabolic pathways during infections with Leishmania are also discussed.

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“…The new inhibitors of ODC are related to 3-aminooxy-1-aminopropane (APA) (15,17,18,24,34), and those of AdoMetDC are derivatives of bis(guanylhydrazones) (29,30,35,36) (Fig. 1).…”

mentioning

confidence: 99%

3-Aminooxy-1-Aminopropane and Derivatives Have an Antiproliferative Effect on Cultured Plasmodium falciparum by Decreasing Intracellular Polyamine Concentrations

Gupta

Krause-Ihle

Bergmann

et al. 2005

Antimicrob Agents Chemother

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The intraerythrocytic development of Plasmodium falciparum correlates with increasing levels of the polyamines putrescine, spermidine, and spermine in the infected red blood cells; and compartmental analyses revealed that the majority is associated with the parasite. Since depletion of cellular polyamines is a promising strategy for inhibition of parasite proliferation, new inhibitors of polyamine biosynthesis were tested for their antimalarial activities. The ornithine decarboxylase (ODC) inhibitor 3-aminooxy-1-aminopropane (APA) and its derivatives CGP 52622A and CGP 54169A as well as the S-adenosylmethionine decarboxlyase (AdoMetDC) inhibitors CGP 40215A and CGP 48664A potently affected the bifunctional P. falciparum ODC-AdoMetDC, with K i values in the low nanomolar and low micromolar ranges, respectively. Furthermore, the agents were examined for their in vitro plasmodicidal activities in 48-h incubation assays. APA, CGP 52622A, CGP 54169A, and CGP 40215A were the most effective, with 50% inhibitory concentrations below 3 M. While the effects of the ODC inhibitors were completely abolished by the addition of putrescine, growth inhibition by the AdoMetDC inhibitor CGP 40215A could not be antagonized by putrescine or spermidine. Moreover, CGP 40215A did not affect the cellular polyamine levels, indicating a mechanism of action against P. falciparum independent of polyamine synthesis. In contrast, the ODC inhibitors led to decreased cellular putrescine and spermidine levels in P. falciparum, supporting the fact that they exert their antimalarial activities by inhibition of the bifunctional ODC-AdoMetDC.

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1-Aminooxy-3-aminopropane, a new and potent inhibitor of polyamine biosynthesis that inhibits ornithine decarboxylase, adenosylmethionine decarboxylase and spermidine synthase

Cited by 43 publications

References 34 publications

Novel Chimeric Spermidine Synthase-Saccharopine Dehydrogenase Gene ( SPE3-LYS9 ) in the Human Pathogen Cryptococcus neoformans

Novel Chimeric Spermidine Synthase-Saccharopine Dehydrogenase Gene ( SPE3-LYS9 ) in the Human Pathogen Cryptococcus neoformans

L-arginine metabolism and its impact on host immunity against Leishmania infection

3-Aminooxy-1-Aminopropane and Derivatives Have an Antiproliferative Effect on Cultured Plasmodium falciparum by Decreasing Intracellular Polyamine Concentrations

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