Scalable Hybrid Synthetic/Biocatalytic Route to Psilocybin

Author: mycolabadmin
6/8/2020
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Summary

Researchers developed a new method to manufacture psilocybin, a promising therapeutic compound from magic mushrooms being tested to treat depression. Instead of using toxic chemicals, they replaced a difficult chemical step with an enzyme from the mushroom itself called PsiK. This approach produced gram amounts of pure psilocybin efficiently and could eventually lower costs for future medical use.

Background

Psilocybin is the principal indole alkaloid of Psilocybe mushrooms currently undergoing clinical trials for treatment-resistant depression and major depressive disorder. Traditional chemical synthesis of psilocybin is problematic due to heavy metal-dependent hydrogenolysis and low-yielding phosphorylation chemistry. The identification of psilocybin biosynthetic genes and enzymes, including the kinase PsiK, has opened new production avenues.

Objective

To develop a scalable hybrid synthetic/biocatalytic route to psilocybin production by replacing problematic chemical phosphorylation with the mushroom kinase PsiK. The study aimed to biochemically characterize PsiK and establish a pilot-scale protocol for recombinant enzyme production suitable for gram-scale psilocybin synthesis.

Results

PsiK was successfully characterized with optimal activity at 40°C and pH 7.0, showing Mg2+ dependency and a catalytic efficiency 3-fold higher for psilocin phosphorylation than biosynthetic substrate. Pilot-scale fermentation yielded 150 mg of pure, active, soluble recombinant PsiK. Gram-scale biocatalytic conversion achieved quantitative conversion of 725 mg psilocin to psilocybin within 20 minutes, yielding 893 mg (88.5% isolated yield) of pure product.

Conclusion

The combined chemical/biocatalytic synthesis eliminates heavy metals and problematic phosphorylation chemistry while combining the simplicity of tryptamine chemistry with enzymatic selectivity. The pilot-scale PsiK production protocol provides a viable path to kilogram-scale psilocybin production at reasonable cost, supporting pharmaceutical and clinical development of this important therapeutic agent.

Published in:Chemistry - A European Journal,
Study Type:Experimental Research,
Source: PMID: 32101345, DOI: 10.1002/chem.202000134