Structure/function studies on two type 1 ribosome inactivating proteins: Bouganin and lychnin

Fermani, Simona; Tosi, Giovanna; Farini, Valentina; Polito, Letizia; Falini, Giuseppe; Ripamonti, A.; Barbieri, Luigi; Bolognesi, Andrea

doi:10.1016/j.jsb.2009.07.010

Cited by 19 publications

(26 citation statements)

References 53 publications

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“…This conformation is very important for RIP activity because this residue has been shown to be responsible for the interaction with the target adenine [18]. Because the active site residues are somewhat conserved amongst saporin isoforms and other RIPs [20], differences in the activity could be attributed to amino acid differences lying outside the active cleft. The mutation of residue Asn 162 to Asp 162 (N162D) is sufficient to significantly reduce saporin-S6 in vitro activity and cytotoxicity.…”

Section: Saporin-s6mentioning

confidence: 99%

Saporin-S6: A Useful Tool in Cancer Therapy

Polito

Bortolotti

Mercatelli

et al. 2013

Toxins

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113

115

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Thirty years ago, the type 1 ribosome-inactivating protein (RIP) saporin-S6 (also known as saporin) was isolated from Saponaria officinalis L. seeds. Since then, the properties and mechanisms of action of saporin-S6 have been well characterized, and it has been widely employed in the construction of conjugates and immunotoxins for different purposes. These immunotoxins have shown many interesting results when used in cancer therapy, particularly in hematological tumors. The high enzymatic activity, stability and resistance to conjugation procedures and blood proteases make saporin-S6 a very useful tool in cancer therapy. High efficacy has been reported in clinical trials with saporin-S6-containing immunotoxins, at dosages that induced only mild and transient side effects, which were mainly fever, myalgias, hepatotoxicity, thrombocytopenia and vascular leak syndrome. Moreover, saporin-S6 triggers multiple cell death pathways, rendering impossible the selection of RIP-resistant mutants. In this review, some aspects of saporin-S6, such as the chemico-physical characteristics, the structural properties, its endocytosis, its intracellular routing and the pathogenetic mechanisms of the cell damage, are reported. In addition, the recent progress and developments of saporin-S6-containing immunotoxins in cancer immunotherapy are summarized, including in vitro and in vivo pre-clinical studies and clinical trials.

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Section: Saporin-s6mentioning

confidence: 99%

Saporin-S6: A Useful Tool in Cancer Therapy

Polito

Bortolotti

Mercatelli

et al. 2013

Toxins

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113

115

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“…A detailed structural analysis of the N- and C-terminal domains indicated that the efficiency of saporin-6 on various polynucleotides could be ascribed to a negative electrostatic surface potential at the active site and several exposed positively charged residues in the region around that site. These two conditions, which are not present at the same time in the other examined RIPs, would guarantee an efficient interaction with the substrate and efficient catalysis [59]. The debate is still open as to whether or not RIPs possess enzymatic activities other than N-glycosidase or PNAG, such as RNAase and/or DNAase activities [6].…”

Section: Biochemical Characteristicsmentioning

confidence: 99%

“…In addition, when mamalian cells were exposed to seed-extracted saporin and rRNA was extracted from intoxicated cells, rRNA was found to be depurinated at a single site, most likely the one corresponding to the alpha sarcin-ricin target [64]. Removal of a second adenine residue or more adenine residues has also been reported for saporin-6 and saporin L1, respectively [59,63]. Analysis of the in vivo activity of other saporin isoforms (such as L1) [63] will be required to assess whether multiple depurination events play any major role in the mammalian cell’s intoxication process.…”

Section: Biochemical Characteristicsmentioning

confidence: 99%

Ribosome-Inactivating Proteins: From Plant Defense to Tumor Attack

Virgilio

Lombardi

Caliandro

et al. 2010

Toxins

145

128

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Ribosome-inactivating proteins (RIPs) are EC3.2.32.22 N-glycosidases that recognize a universally conserved stem-loop structure in 23S/25S/28S rRNA, depurinating a single adenine (A4324 in rat) and irreversibly blocking protein translation, leading finally to cell death of intoxicated mammalian cells. Ricin, the plant RIP prototype that comprises a catalytic A subunit linked to a galactose-binding lectin B subunit to allow cell surface binding and toxin entry in most mammalian cells, shows a potency in the picomolar range. The most promising way to exploit plant RIPs as weapons against cancer cells is either by designing molecules in which the toxic domains are linked to selective tumor targeting domains or directly delivered as suicide genes for cancer gene therapy. Here, we will provide a comprehensive picture of plant RIPs and discuss successful designs and features of chimeric molecules having therapeutic potential.

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“…are not named yet. Above all, there are further variants for each of the named type I RIPs slightly differing in the amino acid sequences (Bolognesi et al, 1995;Fermani et al, 2009). Saponin bearing herbs are also a problem for grazing cattle.…”

Section: Properties Of Saponins Occurring In Caryophyllaceae and Illementioning

confidence: 99%