Polyamines as Targets for Therapeutic Intervention

Marton, Laurence J.; Pegg, Anthony E.

doi:10.1146/annurev.pa.35.040195.000415

Cited by 626 publications

(403 citation statements)

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“…They had been released because the affinity of the polyamines for the GlcNH 3 ϩ -enriched HS of Gpc-1 had been diminished. In keeping with these results, DFMO treatment is known to increase both the V max and K m for polyamine binding to the putative transporter, which means increased capacity for polyamine uptake, but reduced overall affinity (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11).…”

Section: Involvement Of Gpc-1 In Sperminementioning

confidence: 57%

“…An excess of intracellular polyamines induces expression of antizyme, which forms a complex with ornithine decarboxylase, leading to rapid degradation of ornithine decarboxylase, thereby constituting a negative feedback loop. A decrease in the polyamine content of cells leads to a marked increase in the rate of polyamine uptake from the environment (1)(2)(3)(4)(5)(6)(7)(8)34). Antizyme is also involved in polyamine transport by inhibiting uptake and by stimulating excretion (34).…”

Section: Discussionmentioning

confidence: 99%

“…Cells (even uptake-deficient cells) can also secrete polyamines (for reviews, see Refs. [1][2][3][4][5][6][7][8]. Polyamine transport proteins and their genes have been identified in prokaryotes (9).…”

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confidence: 99%

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Glypican-1 Is a Vehicle for Polyamine Uptake in Mammalian Cells

Belting

Mani

Jönsson

et al. 2003

Journal of Biological Chemistry

150

113

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Polyamines (putrescine, spermidine, and spermine) are essential for growth and survival of all cells. When polyamine biosynthesis is inhibited, there is up-regulation of import. The mammalian polyamine transport system is unknown. We have previously shown that the heparan sulfate (HS) side chains of recycling glypican-1 (Gpc-1) can sequester spermine, that intracellular polyamine depletion increases the number of NO-sensitive N-unsubstituted glucosamines in HS, and that NO-dependent cleavage of HS at these sites is required for spermine uptake. The NO is derived from S-nitroso groups in the Gpc-1 protein. Using RNA interference technology as well as biochemical and microscopic techniques applied to both normal and uptake-deficient cells, we demonstrate that inhibition of Gpc-1 expression abrogates spermine uptake and intracellular delivery. In unperturbed cells, spermine and recycling Gpc-1 carrying HS chains rich in Nunsubstituted glucosamines were co-localized. By exposing cells to ascorbate, we induced release of NO from the S-nitroso groups, resulting in HS degradation and unloading of the sequestered polyamines as well as nuclear targeting of the deglycanated Gpc-1 protein. Polyamine uptake-deficient cells appear to have a defect in the NO release mechanism. We have managed to restore spermine uptake partially in these cells by providing spermine NONOate and ascorbate. The former bound to the HS chains of recycling Gpc-1 and S-nitrosylated the core protein. Ascorbate released NO, which degraded HS and liberated the bound spermine. Recycling HS proteoglycans of the glypican-type may be plasma membrane carriers for cargo taken up by caveolar endocytosis.

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Section: Involvement Of Gpc-1 In Sperminementioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

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Glypican-1 Is a Vehicle for Polyamine Uptake in Mammalian Cells

Belting

Mani

Jönsson

et al. 2003

Journal of Biological Chemistry

150

113

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“…Overexpression of AzI provides growth advantage and causes cell transformation High levels of ODC activity and high cellular content of polyamines are hallmarks of cell transformation (Marton and Pegg, 1995). As AzI directly inhibits Az and thereby upregulates ODC levels (Murakami et al, 1989) and, possibly, polyamine transport, we predicted that AzI might be an important regulator of cellular proliferation and transformation.…”

Section: Resultsmentioning

confidence: 99%

Overexpression of antizyme-inhibitor in NIH3T3 fibroblasts provides growth advantage through neutralization of antizyme functions

et al. 2006

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Antizyme inhibitor (AzI) is a homolog of ornithine decarboxylase (ODC), a key enzyme of polyamine synthesis. Antizyme inhibitor retains no enzymatic activity, but exhibits high affinity to antizyme (Az), a negative regulator of polyamine homeostasis. As polyamines are involved in maintaining cellular proliferation, and since AzI may negate Az functions, we have investigated the role of AzI in regulating cell growth. We show here that overexpression of AzI in NIH3T3 cells increased growth rate, enabled growth in low serum, and permitted anchorage-independent growth in soft agar, while reduction of AzI levels by AzI siRNA reduced cellular proliferation. Moreover, AzI overproducing cells gave rise to tumors when injected into nude mice. AzI overexpression resulted in elevation of ODC activity and of polyamine uptake. These effects of AzI are a result of its ability to neutralize Az, as overexpression of an AzI mutant with reduced Az binding failed to alter cellular polyamine metabolism and growth properties. We also demonstrate upregulation of AzI in Ras transformed cells, suggesting its relevance to some naturally occurring transformations. Finally, increased uptake activity rendered AzI overproducing and Ras-transformed cells more sensitive to toxic polyamine analogs. Our results therefore imply that AzI has a central and meaningful role in modulation of polyamine homeostasis, and in regulating cellular proliferation and transformation properties.

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“…6 This is thought to be mainly due to the short half-lives of the main regulatory enzymes, ODC and AdoMetDC. 4 and 7 In contrast, inhibition of ODC by DL-α-difluoromethylornithine (DFMO) is successfully used to treat African sleeping sickness caused by Trypanosoma brucei gambiense, thereby validating polyamine metabolism as an antiparasitic target in these protozoan parasites.…”

mentioning

confidence: 99%

Structural and mechanistic insights into the action of Plasmodium falciparum spermidine synthase

Burger

Birkholtz

Joubert

et al. 2007

Bioorganic & Medicinal Chemistry

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Spermidine synthase is currently considered as a promising drug target in the malaria parasite, Plasmodium falciparum, due to the vital role of spermidine in the activation of the eukaryotic translation initiation factor (eIF5A) and cell proliferation. However, very limited information was available regarding the structure and mechanism of action of the protein at the start of this study. Structural and mechanistic insights of the P. falciparum spermidine synthase (PfSpdSyn) were obtained utilizing molecular dynamics simulations of a homology model based on the crystal structures of the Arabidopsis thaliana and Thermotoga maritima homologues. Our data are supported by in vitro site-directed mutagenesis of essential residues as well as by a crystal structure of the protein that became available recently. We provide, for the first time, dynamic evidence for the mechanism of the aminopropyltransferase action of PfSpdSyn. This characterization of the structural and mechanistic properties of the PfSpdSyn as well as the elucidation of the active site residues involved in substrate, product, and inhibitor interactions paves the way toward inhibitor selection or design of parasite-specific inhibitors. openUP -February 2007 Graphical abstractArticle Outline

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Polyamines as Targets for Therapeutic Intervention

Cited by 626 publications

References 0 publications

Glypican-1 Is a Vehicle for Polyamine Uptake in Mammalian Cells

Glypican-1 Is a Vehicle for Polyamine Uptake in Mammalian Cells

Overexpression of antizyme-inhibitor in NIH3T3 fibroblasts provides growth advantage through neutralization of antizyme functions

Structural and mechanistic insights into the action of Plasmodium falciparum spermidine synthase

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