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Sweet Almonds: One Amino Acid Did the Trick

Well, I spent the holiday weekend here sending out pictures of food on my Twitter account, so I suppose it’s only fitting that I blog about a related topic today. But it also touches on metabolic enzymes, transcription factors, and death by cyanide, so there’s something for most everyone.

I refer to this paper which appeared recently in Science, where a multinational team (Spain, Denmark, Italy, Switzerland) reveals something that’s been a puzzle for a long time: how did almonds manage to get domesticated? There’s evidence for almond consumption by humans going back thousands of years, and the details are still being worked out. But what’s for sure is that typical wild almonds are not fit to eat. They’re bitter, for one thing, and they’ll kill you even if for some reason you don’t mind the taste (5 to 10 of them could be fatal to a small child). The bitterness is from amygdalin, a cyanogenic glycoside found in a number of related plant species (for example, the pits of peaches and apricots). Those are toxic, too – there are ancient Egyptian records of the capital penalty of “death by peach”, for example – but since no one is tempted to eat peach pits rather than the peach fruit, it’s not much of a problem. Almonds, though, feature the seed as the edible part itself, which is unique among the edible Rosaceae species.

Amygdalin breaks down pretty readily – it’s a cyanohydrin of benzaldehyde and a molecule of gentebiose (glucose disaccharide), and crushing up the kernals (as in eating them!) liberates beta-glucosidase that cleaves off the sugar molecules. What you’re left with is after enzymatic cleavage is benzaldehyde, its cyanohydrin (mandelonitrile), and some free HCN floating around – with more to come, unfortunately, if you’ve swallowed the stuff. The mixture can be processed to edible almond syrup (orgeat), or almond extract, which are basically edible preparations of benzaldehyde, but you have to know what you’re doing. As with cassava (which also contains cyanogenic glycosides), local cultures worked out ways to treat the plant material to render it nonlethal, but it would of course be a bit more straightforward if the stuff weren’t poisonous to begin with.

Enter the sweet almond. But how? This is a mutant form of the almond tree that doesn’t produce the cyanogeneic glycosides, and these are (of course) the almonds you’ve been consuming all your life. This cultivar spread throughout much of the ancient world. Almond trees start bearing relatively soon compared to (say) the occasional sweet-acorn oak tree mutants known in the wild (no cyanide there, just bitterness), and were thus domesticated rapidly. In modern times, the “Sk” gene locus (“sweet kernal”) had been worked out to a fuzzy level of detail, but the complications of plant genetics left its real identity unknown. Until now. This new paper reports a draft genome of the cultivated almond, and shows that there’s actually a transcription factor mutation (bHLH2) that does the trick.

Transcription factor fans will note from that name that it’s a basic helix-loop-helix protein, which work by dimerizing through leucine-zipper interactions to form active transcriptional complexes. The mutation in this case lead to a Phe-for-Leu and Arg-for-Leu, mutations, which cause enough problems (especially the first one) to make the protein transcriptionally incompetent. Downstream of that, two CYP p450 enzymes are no longer expressed that are crucial to amygdalin synthesis (they do the phenylalanine-to-mandelonitrile part, via phenylacetaldehyde oxime). So in the end, we owe edible almonds to a change in a single amino acid side chain. This sort of mutation has surely popped up in the wild from time to time, but you’d expect it to be pretty strongly selected against, since such a plant’s seeds will tend to get eaten rather than be allowed to sprout. Until we came along, that is.

I like the fact that this paper directly cites Pliny the Elder (I wonder how many cites he picks up these days) about Roman technique of detoxifying bitter almonds, but of course he also mentions the sweet ones, albeit noting that they’re less medicinal. Bitter almond extract has been used up to modern times as a remedy, but if it’s not processed sufficiently it can have significant amounts of cyanide in it – and if it is processed well, it’s just benzaldehyde. Meanwhile, mention of medicinal effects compels me to note that the mono-glucose form of amygdalin is (infamously) known as laetrile, which is still being hawked to the desperate and/or the gullible as a supposed cancer cure. It’s useless. It’s been shown to be useless over and over, but it’s still out there, sadly, shortening the lives of its consumers and removing their money in the process. Stick with the almonds that don’t make cyanide!

16 comments on “Sweet Almonds: One Amino Acid Did the Trick”

  1. Once a Chemist says:

    I cited Pliny the Elder in my thesis (and though that was awhile ago, there is no truth to the rumor that he was a contemporary). I was providing background on several natural products, and Pliny and a couple of the other ancients made it into the references, as did the Marquis de Sade, who is probably cited even less often in the chemical literature. The Marquis connection was to cantharides/cantharidin.

  2. Molmechanic says:

    Apple and pear seeds also contain amygdalin. You can’t get poisoned from eating one apple core, but there was a case where an individual was poisoned after eating a cupful of apple seeds that he had saved up over time.

  3. Diver Dude says:

    I cited the lyrics from “Your latest trick” by Dire Straits in my PhD thesis. Also, Mark Twain’s observation on the wonders of science on the dedication page. That one damn nearly got me failed at my viva. Who knew crusty old professors of psychopharmacology have no sense of humour?

    1. G2 says:

      My phrase on the dedication page was:
      Research is like sex: it is more talked about
      than performed since to be really satisfactory
      its practie requires not only interest and pleasure
      but hard work.

      I had no problems with it, probably because it was correctly cited:
      J. Irreproducible Results 1998, 43(2), 10

  4. Derek Freyberg says:

    Has anyone dared to put some of the lyrics from Tom Lehrer’s “Lobachevsky” in their thesis? – you know the ones, with a Russki accent:
    “I am never forget the day I first meet the great Lobachevsky.
    In one word he told me secret of success in mathematics:
    Plagiarize!

    Only be sure always to call it please ‘research’.”?
    I was tempted, but refrained, even though I’d heard about Tom Lehrer from the head of the department, who had a collection of Lehrer’s records.

    1. NoLongerBreathedIn says:

      Yair N. Minsky has. Also some other lyrics.

  5. sgcox says:

    Dear Derek,
    This is a filthy slur on the Great Mathematician. If not, please substantiate.

    1. loupgarous says:

      You haVe but to ask, and wikipedia comes to your aid like a faithful servant:

      Lobachevsky is the subject of songwriter/mathematician Tom Lehrer’s humorous song “Lobachevsky” from his Songs by Tom Lehrer album. In the song, Lehrer portrays a Russian mathematician who sings about how Lobachevsky influenced him: “And who made me a big success / and brought me wealth and fame? / Nikolai Ivanovich Lobachevsky is his name.” Lobachevsky’s secret to mathematical success is given as “Plagiarize!”, as long as one is always careful to “call it, please, research”. According to Lehrer, the song is “not intended as a slur on [Lobachevsky’s] character” and the name was chosen “solely for prosodic reasons”

      In Poul Anderson’s 1969 fantasy novella “Operation Changeling” – which was later expanded into the fix-up novel Operation Chaos (1971) – a group of sorcerers navigate a non-Euclidean universe with the assistance of the ghosts of Lobachevsky and Bolyai. The story also contains the line, “Nikolai Ivanovich Lobachevsky is his name,” possibly a nod to the Tom Lehrer song.

  6. Anonymous says:

    sgcox: The Lobachevsky comment is from an old (1960s) humorous song. Further explained here:
    https://math.stackexchange.com/questions/119123/motivation-for-tom-lehrers-song-lobachevsky

    When Derek posts about tox, he might consider referencing Lehrer’s “Poisoning Pigeons in the Park.” And EVERY chemist knows “The Elements.” Many PhD students know “Masochism Tango.”

  7. Young Padawan says:

    Some recent Scopus Citation numbers of Pliny the Elder:
    2019: 38
    2018: 74
    2017: 118
    2016: 90
    2015: 103
    2014: 82
    2013: 104
    2012: 95
    2011: 76
    2010: 79
    2009: 77

  8. Neil Withers says:

    Pliny also gets cited in this JACS article about lead sulfide by the late Paul O’Brien:
    https://pubs.acs.org/doi/10.1021/ja804516q

    Presumably this passage:
    https://www.loebclassics.com/view/pliny_elder-natural_history/1938/pb_LCL394.253.xml?readMode=recto

  9. Ursa Major says:

    He is sometimes cited as Plinius (or Plinius Major, or Plinius Secundus). Searching “pliny” OR “plinius” finds 411 from 2018. Understandably most are from the broad subject area of Humanities, but Scopus finds 23 from Medicine and 7 from Chemistry.

    Aristotle has him well beaten though, with 572 references in 2018 in Medicine or Chemistry.

  10. anonymous says:

    folks: off topic discussion. Is there is any forum or site wherein I can vent my angst against Chinese company that is operating in the US? They serially violate the norms of delivery or the quality of the chemical, that I would like to bring it to notice to all. They bait you with specialized chemical availability and then you are stuck. Did it happen to any one and am dead serious!

  11. Ian Malone says:

    As with cassava (which also contains cyanogenic glycosides), local cultures worked out ways to treat the plant material to render it nonlethal, but it would of course be a bit more straightforward if the stuff weren’t poisonous to begin with.

    Any others? Taro: okay if thoroughly boiled, intensely painful if not. Ackee: potentially lethal if not ripe. Rhubarb (of all things!): calcium oxalate in the leaves, not exactly lethal acutely, but you wouldn’t want them in your salad. Many, many beans uncooked: vomiting and diarrhoea.

    I’ve always wondered about the “bitter almonds” description of the smell of cyanide, most people don’t have much exposure to the bitter variety.

    1. Anonymous says:

      As a kid, I was taught to never eat raw plantains; always cook them first (or buy a bag of precooked plantain chips). The implication was that raw plantains are somehow poisonous. Googling discloses that it is more a matter of taste, not toxicity.

  12. milkshake says:

    Death by peach: When you make your own plum brandy, it is best to keep some plums whole with pits, and pit the rest – benzaldehyde and cyanide from the kernel add flavor to the product (but there is too much of it for a fine slivowitz if made from whole plums only).

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