LSD Precursor From Baker’s Yeast
    By Enrico Uva | June 29th 2011 10:23 PM | 6 comments | Print | E-mail | Track Comments
    About Enrico

    I majored in chemistry, worked briefly in the food industry and at Fisheries and Oceans. I then obtained a degree in education. Since then I have...

    View Enrico's Profile
    Lysergic acid is the natural precursor of all therapeutic ergot alkaloids. These include not only include the hallucinogenic lysergic acid diethylamide(LSD) but drugs used to treat senile dementia, migraines, pituitary tumors, Parkinson's disease, type 2 diabetes and also ergometrine, which is used to induce labor and alleviate postpartum hemmorhage.

    What the molecules of all these drugs have in common is their precursor's four-ring combination, the so-called tetracyclic ergoline ring system. The unique substituent is what determines if the chemical is a brain vasodialator(nicergoline) or a womb-contractor(ergometrine). Notice the strong molecular resemblance between ergometrine and LSD.  It may come as a surprise to some that unlike LSD, lysergic acid acts as a depressant.

    Various cereal gases such as wheat and rye can be attacked by ergot fungi of the genus Claviceps. When a mature ergot kernel drops to the ground, the fungus remains dormant until proper conditions trigger the growth of fruiting bodies, which are the source of the alkaloids.

    Lysergic acid is one of those alkaloids synthesized by ergot fungi, but they also have the cellular machinery to convert the material into other compounds.

    This explains why in the current industrial method of lysergic acid production, in which decaying matter fuels fermentations of Claviceps cultures, the lysergic acid has to be purified. Pharmaceutical companies make forty thousand pounds of it every year.

    But is there hope for a more efficient method of production?

    In the species Claviceps purpurea, the biosynthetic pathway to lysergic acid is relatively straightforward. It begins with L-tryptophan, the same amino acid that serves as the human precursor to the neurostransmitter serotonin. Four steps later, an intermediate known as chanoclavine-i aldehyde appears, a substance that is also synthesized by other fungi. Just last year (2010), Matuschek, Wallwey, Li and their group succeeded in using an E.coli-cloned Claviceps enzyme and enzyme-free gluthathione to convert the intermediate into agroclavine in vitro. In vivo, Claviceps purpurea follows up agroclavine synthesis with a double bond rearrangement and oxidation to arrive at the lysergic acid intermediate.

    When does the baker's yeast enter the picture?

    By using gene cloning and genome mining (by inactivating genes to test if they indeed lead to production of key enzymes), researchers have identified the 14-gene cluster that is responsible for the synthesis of lysergic acid. Edwin Wintermute and Pam Silver at Harvard's Department of Systems Biology are in the process of sneaking that section of Claviceps genome into baker's yeast to get it to produce lysergic acid. Moreover, each of the 43 species of Claviceps uses a different series of enzymes to convert lysergic acid into various amides or peptides.

    The ambitious Wintermute is hoping that the coexpression of these enzymes along with controlled mutations and shuffling of genetic domains will be used to create huge libraries of new bioactive ergot alkaloids.

    A little side note: After a few days of trying to contact Edwin(Jake)Wintermute, I eventually got a reply. He apologized for not checking his email while he was on vacation. Where was he? Ironically, exactly where I usually am, in Montreal!


    Matuschek, Marco. Wallwey, Christiane. Xie, Xiulan. Li, Shu-Ming. New Insights into Ergot Alkaloid Biosynthesis... Org. Biomol.Chem, 2011 9,4328

    Wintermute, Edwin. Silver, Pam. Conference Poster for Synthetic Biology 5 Conference at Stanford University. June 2011

    The Merck Index


    Various cereal gases such as wheat and rye ...
    Breakfast cereals come in ever more surprising variants. I fear, inhaling breakfast may direct kids down a slippery slope.
    It must be the reason why, at age 50, I still enjoy cereal! :)
    I suggested this exact idea some five or ten years ago on a mycology forum, among others. Wintermute is just stealing my ingenious scheme.

    Is it possible that others also came up with the idea in the same time frame?

    No. Categorically. :P

    More seriously, yes, of coarse. However, the fora on which the idea was discuss are not what would be considered 'reference worthy'; i.e. one of the main topics of discussion is drugs. Hence, there would be a reluctance for Wintermute to admit the idea originating from such.

    However, saying that, my own tutor in mycology insisted on us reading his own journal entry to see what kind of level of quality was required. In this entry he had failed to fully sterilise a soil sample. The irony being, this is quite a common task for said fora.

    To sterilise the sample, he would ideally be using a vacuum autoclave, incubation prior to sterilisation (to germinate the offending organisms from spores into their more vulnerable form) and at least a 45 minute cycle, as opposed to the normal 15 minute run used for surgical instruments. This is information he could have easily gleaned from 'not journal worthy' sources.

    Maybe it's time for a follow up blog (interview) post ? I haven't heard anything new regarding this topic nor do journals return any hits for Wintermute's 2011 & 2012 literature.