When nature turns deadly: A look at Abrin

Artwork in monoprint with digital overlay using the software Procreate with the bright red colour signifying the beans of Abrus precatorius

Mon, 10/02/2023 - 09:46

What is abrin?

In certain parts of Asia and Australia, grows a flowering plant of the bean family Fabaceae, known as Abrus precatorius, also more commonly as jequirity bean or rosary pea [1]. It’s a delicate, perennial climber but extremely invasive and classified as a weed in several countries. However, what stands out for this seemingly unremarkable plant are the brightly coloured seeds (Fig 1). Little do people know that the bright red seeds contain the extremely toxic poison, abrin. The poison is so lethal that the ingestion of a single seed of the rosary pea may be fatal for an adult human [2].

Brightly coloured seeds from Abrus precatorius, (Getty Images/iStockphoto) — **Figure 1**: Brightly coloured seeds from Abrus precatorius, more commonly known as rosary pea. The bright sed seeds act as the only natural source of the highly potent poison, abrin. (Getty Images/iStockphoto)

Structural insights into abrin

The water-soluble protein, abrin, acts as a ribosome-inhibiting protein (RIP). This is similar to the mode of action of another lethal poison, ricin, that is found naturally in castor beans [3]. Abrin, has a molecular weight of ~63,000 Da and is composed of two polypeptide chains of similar size- chains A and B, that are bridged by a disulphide bond (Figure 2a). Chain A is the site of N-glycosidase activity, whereas chain B demonstrates carbohydrate-binding (lectin) properties. Chemically, abrin is a mixture of four toxins: abrin-a (https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P11140), abrin-b (Q06077), abrin-c (P28590), and abrin-d (Q06076). Abrin-a is the most potent of the four isotoxins. Despite having a similar molecular weight (~65000 Da) and mode of action to ricin, abrin is around 75 times more toxic (4, Figure 2b).

Mode of action

Abrin-a catalyzes the removal of an adenine base from A4324 of the 28S rRNA by hydrolyzing the adenine-ribose N-glycosidic bond. This adenine (A4324) is present within the GAGA tetraloop motif of the sarcin-ricin loop (SRL) that is highly conserved within the eukaryotic 28S rRNA [5]. As a result of the adenine base removal from A4324, eukaryotic ribosomes become unable to bind to elongation factors and this leads to termination of protein synthesis at the elongation step, which ultimately leads to cell death [6].

The overall fold of abrin-a consists of three folding domains. Domain 1 is present at the N-terminus, domain 2 consists of residues 110-197 and domain 3 makes up the C-terminus region of the protein [7]. Five residues- Tyr-74, Tyr-113, Glu-164, Arg-167, and Trp-198, that are present at the active site are conserved throughout all RIPs (Figure 3). The reorganization of the active site cleft, as a result of binding to A4324, causes the transition of Tyr-74 from closed to open conformation [8].

Mode of action of abrin — **Figure 3**: (A) Cartoon representation of abrin-a:SRL model indicating binding of GA4324G4325A tetraloop motif of SRL(yellow) to abrin-a active site cleft. (B) Surface of abrin-a is drawn to illustrate the binding of adenine and guanine bases of residues A4324 (cyan) and G4325 (magenta), from GA4324G4325A tetraloop motif SRL (yellow), into the primary (red) and secondary (pink) pockets at abrin-a active site cleft. (Source: Bansia H, Bagaria S, Karande AA, Ramakumar S. Structural basis for neutralization of cytotoxic abrin by monoclonal antibody D6F10. FEBS J. 2019, 286 (5), 1003-1029)

Unfortunately, there are no known antidotes for abrin. However, a recent study has reported that a monoclonal antibody, D6F10 neutralizes the toxicity of abrin-a [8]. The abrin-DCF10 complex is stabilized by various electrostatic interactions. In presence of this antibody, abrin-a is incapable of accessing the SRL on the eukaryotic 28S rRNA because the ribosome cannot sterically accommodate the abrin-D6F10 complex (Figure 4).

Interaction of abrin with the antibody D6F10 — **Figure 4**: (A) Cartoon representation of the abrin-a:D6F10 model indicating binding of D6F10 to abrin-a. (B) Molecular interactions observed at abrin-a:D6F10 interface. (Source: Bansia H, Bagaria S, Karande AA, Ramakumar S. Structural basis for neutralization of cytotoxic abrin by monoclonal antibody D6F10. FEBS J. 2019, 286 (5), 1003-1029)

Symptoms of abrin poisoning

In nature, this lethal toxin is found only in the seeds of the rosary pea where the hard, outer covering protects it from coming into contact with the stomachs of most animals. However, if the seed coat is punctured or injured, it can lead to abrin poisoning. Symptoms of poisoning include diarrhoea, vomiting, colic, tachycardia and tremors. Death usually occurs after a few days due to kidney failure, heart failure, and/or respiratory paralysis. The severity of the effects of abrin poisoning vary depending on the means of exposure to the substance (whether inhaled, ingested, or injected). Exposure to abrin on the skin can cause an allergic reaction, indicated by blisters, redness, irritation, and pain.

Using abrin for cancer treatment

The extremely toxic abrin can also be used as an immunoadjuvant for the treatment of cancer. Adjuvants in immunology are often used to modify or augment the effects of a vaccine by stimulating the immune system to respond to the vaccine more vigorously, and thus providing increased immunity to a particular disease. In one study, the regression of a growing tumour found in colon cancer was observed after abrin was injected into the tumour, while the induction of a strong antitumor immunity also occurred (8, Figure 5).

**Figure 5**: Abrin inhibited tumour growth in vivo. (A) shows the tumour growth in presence of different doses of abrin. (B) is a graphical representation of the tumour sizes which indicate that abrin addition delays tumour growth. (Source: Surendranath K, Karande AA. A neutralizing antibody to the a chain of abrin inhibits abrin toxicity both in vitro and in vivo. Clin Vaccine Immunol. 2008 May;15(5):737-43. doi: 10.1128/CVI.00254-07. Epub 2008 Mar 19. PMID: 18353919; PMCID: PMC2394836)

Therefore, the antitumor effects of abrin are attributable to two kinds of activity: cytotoxicity and adjuvant activity. In a recent in vitro and in vivo study, antibodies specific to the recombinant abrin A-chain were shown to rescue cells from toxicity. Importantly, the antibody also protected mice from lethal doses of the toxin. The neutralising effect of the antibody was shown to be due to interference with abrin attachment to the cell surface [9].

Abrin in biowarfare

Due to the easy availability of abrin and simple extraction methods, abrin is an attractive option as a weapon in biowarfare. Abrin is a stable substance, meaning that it can last for a long time in the environment despite extreme conditions such as very hot or very cold temperatures. Abrin is not known to have been used in any wars or terrorist attacks as yet. However, it is actually included in Schedule 1 of the Chemical Weapons Convention (CWC) which lists chemicals that can either be used as chemical weapons and have no, or very limited, uses outside of chemical warfare.

Awareness about abrin

Abrin is a lethal poison produced by the rosary pea to provide some degree of natural protection against insects and pests such as aphids. It is important to be aware of the toxic nature of this naturally occurring compound and to be careful if we are around the rosary pea plant. Remember to be careful with the seeds and not to damage the hard outer covering! However, the saying goes ‘Every cloud has a silver lining’. Abrin appears to have tremendous potential as an anti-cancer agent. We can only wait for a day when this lethal toxin can save human lives instead of ending them!

About the artwork

Eden de Bruijn (Year 12) from the Leys School recounted that his inspiration for choosing the protein abrin as the focus of his artwork came from his fascination with botanical medicines and poisons. He was intrigued by this protein’s poisonous properties and its effect at minimal concentrations along with the fact that there are no known cures at present.

The artwork is a monoprint with digital overlay using the software Procreate. The artwork uses the bright red colour that is the actual colour of the seeds containing abrin. The protein structure uses the same colour palette. Eden also added a dripping liquid to represent the poison in the peas and the amount of damage they can cause to the human body.

View the artwork in the virtual 2022 PDB Art exhibition.

You can also check out the new 2023 PDB art exhibition here bit.ly/PDBart2023