Cycasin

 

Cycad revoluta

DNA damaging or genotoxic plant toxins are not just limited to flowering plants and alkaloids. Today, we are going to look at a very old plant toxin, belonging to the Cycadaceae and Zamiaceae family. The Cycads are probably as old as the dinasours, and they have evolved a deadly molecule to protect themselves. I have talked about the biology of Cycad and Zamia in the [Poison Garden], check them out if you’re interested. 

 

Figure 1: Chemical structure of cycasin and macrozamin.

The principal toxins of the Cycad and Zamia are called cycasin and macrozamin, respectively. I have shown their chemical structures in Figure 1. Cycasin is a fairly simple molecule compared to what we have encountered so far. You may be wondering if cycasin is an alkaloid because of the two nitrogen atoms, but it’s not. In fact, we don’t exactly know how cycasin is made by plants, and until then we will treat cycasin as a special case of its own. However, we can confidently classify cycasin and macrozamin as glycosides, which mean that both molecules contain a sugar fragment, and a glycosidic bond. Macrozamin differs from cycasin by having an additional sugar moiety, we call that a disaccharide. Look carefully at the other end of cycasin's structure, which is called a methylazoxymethanol (MAM) fragment. It is the MAM that confers highly toxic property to cycasin and macrozamin, because MAM is very reactive. Plants love to fashion highly reactive toxins with a sugar coating, and that's exactly what's being done here. We will meet more of these next time when we examine the cyanogenic and cardenolide glycosides.

 

Figure 2: Cycasin toxicity, mechanism of action.

Once ingested, the sugar fragment of cycasin is digested, pulling the grenade pin. Follow my reaction pathways in Figure 2 carefully, bonds that break are coloured in red, bonds that form are coloured in pink. After eliminating a molecule of glucose (sugar) from cycasin, we are left with the highly unstable methylazoxymethanol (MAM), which like a grenade, explodes and blasts itself apart spontaneously. In this process, one molecule of MAM turns into 3 principal products, two of which are not really important (formaldehyde and hydroxide ion). The real damage comes from a product called methyldiazonium ion. Remember that azo or aza suffix means nitrogen containing. Methyldiazonium ion  carries a permanent positive charge on its nitrogen atom, which is triple bonded to another nitrogen atom. That makes a strong electrophile yearns to break free, and become molecular nitrogen gas, which is very stable. After all, nitrogen gas makes up 72% of the air we breathe. In order to achieve that, the methyl (CH₃) group of methyldiazonium ion will react with any available nucleophiles, which include negatively charged DNA bases and proteins. In other words, the DNA or protein gets covalently bonded by a –CH₃ group, or becomes methylated. When DNA gets methylated, the genetic codes will be 'read' and ‘translated’ differently, or worse, wrongly. Errors can also occur during the copying of methylated, and that also leads to mutation and cancer. Cycasin and macrozamin primarily affects the brain, liver and kidney. There is no antidote available, and severe poisoning is invariably fatal within a few weeks.

 

Before I end, here’s your homework. In parts of Japan, the pith of Cycad spp. like those of the sago palm (Cycad revoluta) are processed to obtain edible starch called ‘Sago’. The processing often involve repeated boiling of the cycad pitch in water. With your understanding of organic chemistry, and given that water is also an excellent nucleophile, how do you expect the detox mechnisms go? What happens when water is methylated? Also, in the next article, we are going to examine the most lethal of plant toxins, one that can regenerate itself again and again. Brace yourself for more chemistry!