Uncompetitive inhibition by adenine of the RNA-N-glycosidase activity of ribosome-inactivating proteins

Pallanca, Alessandra; Mazzaracchio, R; Brigotti, Maurizio; Carnicelli, Domenica; Alvergna, Paola; Sperti, S; Montanaro, Lucio

doi:10.1016/s0167-4838(98)00019-3

Cited by 13 publications

(9 citation statements)

References 28 publications

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“…This effect would in turn be consistent with the well-described ribotoxic effect of VTs (36). Attempts to address this question Nevertheless, this mechanism is most likely to explain the actions of VTs.…”

Section: Discussionsupporting

confidence: 73%

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Essential Role for Verotoxin in Sustained Stress-Activated Protein Kinase and Nuclear Factor Kappa B Signaling, Stimulated by Escherichia coli O157:H7 in Vero Cells

Cameron¹,

Bingham

Paul³

et al. 2002

Infect Immun

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The effects of Escherichia coli O157:H7 (strains E30480 and PM601) and the associated verotoxins (VTs), VT1 and VT2, on stress-activated protein kinase and nuclear factor kappa B (NF-B) signaling were investigated with Vero cells, which are extremely sensitive to the cytotoxic effects of E. coli O157:H7 in vitro. Cell-free supernatants prepared from E30480 and PM601 cultures and purified VT1 and VT2 stimulated a strong and prolonged (>4-h) activation of both c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase. However, JNK activity stimulated in response to E30480 supernatants was substantially reduced following pretreatment with anti-VT1 and anti-VT2 antibodies, while a VT1 and VT2 gene knockout mutant of PM601 was unable to stimulate JNK activity. E30480 supernatants also caused a sustained activation of NF-B DNA binding, degradation of inhibitory kappa B alpha (IB␣), and an increase in inhibitory kappa B kinase ␣ activity, although PM601 supernatants and VT1 and VT2 had no effect. However, preincubation with VTs prolonged the transient activation of NF-B and IB␣ degradation stimulated by either tumor necrosis factor alpha or interleukin 1␤, while preincubation with anti-VT antibodies prevented the prolonged loss of IB␣ and partially reduced DNA binding in response to E30480 supernatants. These results strongly suggest that in Vero cells, VT plays an essential role in sustained JNK and NF-B signaling in response to E. coli O157:H7 and that this action may underpin their cell-selective cytotoxic effects. These studies also suggest that another component released by strain E30480 contributes to the early activation of JNK and NF-B.

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Section: Discussionsupporting

confidence: 73%

“…Thus, while JNK alone may not be responsible for VT-induced cytotoxicity, it may determine the rate of cell death by acting in synergy with other events. These events may include activation of caspases and inhibition of protein synthesis, both of which have been shown to be regulated by VTs (12,23,26,36).…”

Section: Discussionmentioning

confidence: 99%

Essential Role for Verotoxin in Sustained Stress-Activated Protein Kinase and Nuclear Factor Kappa B Signaling, Stimulated by Escherichia coli O157:H7 in Vero Cells

Cameron¹,

Bingham

Paul³

et al. 2002

Infect Immun

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“…The catalytic A subunit of ricin exhibits higher affinity, in terms of lower K m values, for the substrate molecules for its adenosine N ‐glycosidase activity, beginning with intact rat liver 80S ribosomes ( K m 2.6 μM), followed by 28S rRNA ( K m 5.8 μM) and various synthetic stem‐loop oligonucleotides ( K m 0.7 – 15.2 μM) (Endo and Tsurugi 1988; Amukele and Schramm 2004). The A subunit also exhibits affinity for adenine (Pallanca and others 1998)—the end product of the ricin‐catalyzed N‐glycosidase reaction—via uncompetitive inhibition ( K iu 30 μM). The ricin B subunit binds free galactose ( K d 35 μM), lactose ( K d 29 μM), and the galactosyl residues of glycoproteins and glycolipids (Houston and Dooley 1982; Simmons and others 1986; Gustafson 2003).…”

Section: Resultsmentioning

confidence: 99%

Thermal Stability of Ricin in Orange and Apple Juices

Jackson

Zhang

Tolleson

2010

Journal of Food Science

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“…All of the aforementioned toxins except Sti, belong to a group of polypeptide enzymes that catalytically inactivate protein synthesis leading to cell death and therefore are transclocated to the cytosol by various mechanisms. The moschatin and the ricin A subunit are type I Ribosome Inactivating Proteins (RIP) and type II respectively, killing cells by N-glycosidases which depurinate the universally conserved alpha-sarcin loop of large rRNAs thus inactivating the 28S subunit of eukaryotic ribosomes [109][110][111][112]. The mechanisms of DT and PE are similar when ADPribosylating eukaryotic elongation factor (EF)-2 at a "diphthamide" residue located at His415, using NAD + as a cofactor [113,114].…”

Section: The Toxin Moietymentioning

confidence: 99%

Antibodies and their Fragments as Anti-Cancer Agents

Schaedel

Reiter

2006

CPD

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The recent developments in the field of recombinant DNA, protein engineering and cancer biology, have let us gain insight into many cancer-related mechanisms. Moreover, novel techniques have facilitated tools allowing unique distinction between malignantly transformed cells, to regular ones. This understanding has paved the way for the rational design of a new age of pharmaceuticals; monoclonal antibodies and their fragments. Antibodies can select antigens on both a specific and high affinity account, and further implementation of these qualities is used to target cancer cells by specifically identifying exogenous antigens of cancer cell populations. The structure of the antibody provides plasticity resonating from its functional sites. Upon binding to the Fc Receptor on effector cells, the crystallisable fragment (Fc) region elicits the onslaught of Antigen Dependent Cell-mediated Cytotoxicity (ADCC) and the plasma-native Complement Dependent Cytotoxicity (CDC) response and apoptosis. The progenitor form of the antibody can evolve in to a tailored therapeutic molecule with the help of recombinant DNA technology. Recombinant antibodies may be linked to potent toxins or radio-labeled fragments, conferring a high killing capability. Other recombinant techniques such as ADEPT, conjugate the specificity of antibodies to a prodrug-catalytic subunit thus creating a high local concentration of an activated chemotherapeutic. Antibodies can be used to recruit the adaptive immune response by binding the antibody fragment to a recombinant MHC molecule displaying a highly immunogenic peptide. Apart from their therapeutic capabilities antibodies are powerful detection tools as observed in the operating theater in a procedure known as Radio-immuno-guided Surgery (RIGS).

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Uncompetitive inhibition by adenine of the RNA-N-glycosidase activity of ribosome-inactivating proteins

Cited by 13 publications

References 28 publications

Essential Role for Verotoxin in Sustained Stress-Activated Protein Kinase and Nuclear Factor Kappa B Signaling, Stimulated by Escherichia coli O157:H7 in Vero Cells

Essential Role for Verotoxin in Sustained Stress-Activated Protein Kinase and Nuclear Factor Kappa B Signaling, Stimulated by Escherichia coli O157:H7 in Vero Cells

Thermal Stability of Ricin in Orange and Apple Juices

Antibodies and their Fragments as Anti-Cancer Agents

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