Structure-Based Design of Ricin Inhibitors

Jasheway, K.R.; Pruet, Jeff M.; Anslyn, Eric V.; Robertus, Jon D.

doi:10.3390/toxins3101233

Cited by 34 publications

(27 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the plant, ricin is translated as a single 66-kDa polypeptide chain protein that is activated intracellularly by proteolytic cleavage to form the active 32-kDa A chain containing enzymatic activity [153,154]. The B chain is essential for the toxin’s entry into the cell [155].…”

Section: Ricinmentioning

confidence: 99%

Review of the Inhibition of Biological Activities of Food-Related Selected Toxins by Natural Compounds

Friedman

Rasooly

2013

Toxins

View full text Add to dashboard Cite

There is a need to develop food-compatible conditions to alter the structures of fungal, bacterial, and plant toxins, thus transforming toxins to nontoxic molecules. The term ‘chemical genetics’ has been used to describe this approach. This overview attempts to survey and consolidate the widely scattered literature on the inhibition by natural compounds and plant extracts of the biological (toxicological) activity of the following food-related toxins: aflatoxin B1, fumonisins, and ochratoxin A produced by fungi; cholera toxin produced by Vibrio cholerae bacteria; Shiga toxins produced by E. coli bacteria; staphylococcal enterotoxins produced by Staphylococcus aureus bacteria; ricin produced by seeds of the castor plant Ricinus communis; and the glycoalkaloid α-chaconine synthesized in potato tubers and leaves. The reduction of biological activity has been achieved by one or more of the following approaches: inhibition of the release of the toxin into the environment, especially food; an alteration of the structural integrity of the toxin molecules; changes in the optimum microenvironment, especially pH, for toxin activity; and protection against adverse effects of the toxins in cells, animals, and humans (chemoprevention). The results show that food-compatible and safe compounds with anti-toxin properties can be used to reduce the toxic potential of these toxins. Practical applications and research needs are suggested that may further facilitate reducing the toxic burden of the diet. Researchers are challenged to (a) apply the available methods without adversely affecting the nutritional quality, safety, and sensory attributes of animal feed and human food and (b) educate food producers and processors and the public about available approaches to mitigating the undesirable effects of natural toxins that may present in the diet.

show abstract

Section: Ricinmentioning

confidence: 99%

Review of the Inhibition of Biological Activities of Food-Related Selected Toxins by Natural Compounds

Friedman

Rasooly

2013

Toxins

View full text Add to dashboard Cite

show abstract

“…38 Pteroic acid is a modest inhibitor of ricin discovered by virtual screening and has an IC 50 of 600 μ M. 36 A series of inhibitors was designed based on structural data for pterin binding in the specificity pocket, with the most potent inhibitor in this study displaying an IC 50 of 240 μ M. 39 Millard’s group reported a small molecule which protected 20% of cells from death from ricin constructs at a drug concentration of 300 nM, by preventing an active site residue from adopting the active conformation. 40 The strongest inhibitor reported for ricin A-chain has a K d value of 26 nM and was a mimic of the ribocation TS of the ricin reaction determined at pH 4.0.…”

mentioning

confidence: 99%

Transition State Structure of RNA Depurination by Saporin L3

2016

View full text Add to dashboard Cite

Saporin L3 from the leaves of the common soapwort is a catalyst for hydrolytic depurination of adenine from RNA. Saporin L3 is a type 1 ribosome inactivating protein (RIP) composed only of a catalytic domain. Other RIPs have been used in immunotoxin cancer therapy, but off-target effects have limited their development. In the current study, we use transition state theory to understand the chemical mechanism and transition state structure of saporin L3. In favorable cases, transition state structures guide the design of transition state analogues as inhibitors. Kinetic isotope effects (KIEs) were determined for an A14C mutant of saporin L3. To permit KIE measurements, small stem–loop RNAs that contain an AGGG tetraloop structure were enzymatically synthesized with the single adenylate bearing specific isotopic substitutions. KIEs were measured and corrected for forward commitment to obtain intrinsic values. A model of the transition state structure for depurination of stem–loop RNA (5′-GGGAGGGCCC-3′) by saporin L3 was determined by matching KIE values predicted via quantum chemical calculations to a family of intrinsic KIEs. This model indicates saporin L3 displays a late transition state with the N-ribosidic bond to the adenine nearly cleaved, and the attacking water nucleophile weakly bonded to the ribosyl anomeric carbon. The transition state retains partial ribocation character, a feature common to most N-ribosyl transferases. However, the transition state geometry for saporin L3 is distinct from ricin A-chain, the only other RIP whose transition state is known.

show abstract

“…In the plant, ricin is translated as a single 66-kDa polypeptide chain protein that is activated intracellularly by proteolytic cleavage to form the active 32-kDa A chain containing enzymatic activity (3,4). The B chain is essential for the toxin's entry into the cell.…”

mentioning

confidence: 99%

Milk Inhibits the Biological Activity of Ricin

Rasooly

Friedman

2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Ricin is a highly toxic protein produced by the castor plant Ricinus communis. The toxin is relatively easy to isolate and can be used as a biological weapon. There is great interest in identifying effective inhibitors for ricin. In this study, we demonstrated by three independent assays that a component of reconstituted powdered milk has a high binding affinity to ricin. We discovered that milk can competitively bind to and reduce the amount of toxin available to asialofetuin type II, which is used as a model to study the binding of ricin to galactose cell-surface receptors. Milk also removes ricin bound to the microtiter plate. In parallel experiments, we demonstrated by activity assay and by immuno-PCR that milk can bind competitively to 1 ng/ml ricin, reducing the amount of toxin uptake by the cells, and thus inhibit the biological activity of ricin. The inhibitory effect of milk on ricin activity in Vero cells was at the same level as by anti-ricin antibodies. We also found that (a) milk did not inhibit ricin at concentrations of 10 or 100 ng/ml; (b) autoclaving 10 and 100 ng/ml ricin in DMEM at 121 °C for 30 min completely abolished activity; and (c) milk did not affect the activity of another ribosome inactivating protein, Shiga toxin type 2 (Stx2), produced by pathogenic Escherichia coli O157:H7. Unlike ricin, which is internalized into the cells via a galactose-binding site, Stx2 is internalized through the cell surface receptor glycolipid globotriasylceramides Gb3 and Gb4. These observations suggest that ricin toxicity may possibly be reduced at room temperature by a widely consumed natural liquid food.

show abstract

Structure-Based Design of Ricin Inhibitors

Cited by 34 publications

References 51 publications

Review of the Inhibition of Biological Activities of Food-Related Selected Toxins by Natural Compounds

Review of the Inhibition of Biological Activities of Food-Related Selected Toxins by Natural Compounds

Transition State Structure of RNA Depurination by Saporin L3

Milk Inhibits the Biological Activity of Ricin

Contact Info

Product

Resources

About