LSD Precursor From Baker’s Yeast

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.

nicergoline_0

The blue highlights the common structure derived from lysergic acid

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.

Claviceps purpurea, the organism that ferments ergots and produces lysergic acid.

Claviceps purpurea, one of the organism that ferments decaying matter and produces lysergic acid.

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. HErgocristinee apologized for not checking his email while he was on vacation. Where was he? Ironically, exactly where I usually am, in Montreal!
REFERENCES

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

http://www.chemspider.com

Merck Index

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The Etymology And Drugs Of Parsley

My first language is a rough southern Italian dialect, scorned by many Northerners. But what I like about my mother tongue is the connection between some of its vocabulary and Linnaean taxonomy.

Parsley for instance is known as  prezzemolo in standard Italian, but I grew up calling it petrosino. Interestingly parsley’s genus, derived from Latin, is Petroselinum. The modern Italian word also originates from Petroselinum, but obviously the dialect-version of parsley is closer to its roots, pardon the pun. The English word seems to have been influenced by the Old French peresiland by the old English petersilie, which in turn is an offshoot of the Latin.

The Greeks once referred to the herb as petroselinon, which meant “rock celery”, but the modern Greek word is based on the Turkish word maydanoz.

Petroselinum latifolium  photo by Forest and Kim Starr

Petroselinum latifolium; credit Forest&Kim Starr

Now that we know parsley’s etymology, we can investigate its chemistry. Simple distillation equipment may be fine for creating moonshine, but it will not do much to separate the compounds of parsley or of any plant for that matter. What’s needed is the Likens Nickerson Method. The parsley-water mixture is placed in one flask, and a separate flask holds an organic solvent. Both are boiled while being connected to a shared set of columns and condenser. Using dry ice, water is removed from the fractions, and eventually the compounds are separated and identified through good-old gas chromatography-mass spectrometry.

The main volatile component of oils in parsley is apiole (also spelled apiol), C12H14O4 .

All sorts of medicinal properties have been attributed to apiole since the mid-19th century, but in concentrated form it can do a number on your kidneys and liver.
The apiole molecule bears a strong resemblance to another substance found in small quantities in parsley: myristicin.


Myristicin is the notorious alkaloid drug which is also found in nutmeg. In the latter, it is found in a greater percentage and coexists with other natural drugs. In the 1970’s pursuit of altered states inspired many inmates to ingest spoonfuls of the spice. Possible side-reactions include chemotherapy-like vomiting and possibly death, a somewhat high price for hallucinations.

As we compare the structure of parsley’s non-psychoactive apiole to that of myristicin, we notice that one of the methoxy(O-CH3)groups is also replaced with hydrogen.

As is often pointed out in the literature, myrisiticin, although not an alkaloid, is structurally very similar to peyote’s hallucinogen, mescaline. Rather than being part of separate methoxy groups, the oxygens in myristicin form a heterocyclic ring, and in mescaline, the allylic group is in a reduced state and the tail-end carbon is replaced with an amino group.

The similarities in natural products are not coincidences. In their bio-synthesis, they share a common pathway. Side-reactions then occur for various reasons, and they are subject to natural selection.

Molecules, like words, often have common roots, but they are in a constant state of flux.

Sources

  • The Merck Index. Twelfth Edition
  • Pol. J. Food Nutr. Sci. 2005, Vol. 14/55,No 1, pp. 63–66