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