Psilocybin's Enzymatic Pathway

This pathway is particularly great because it:

• is only five enzymatic steps (very few steps relative to other metabolic pathways!)

• begins with tryptophan, which is an amino acid, a basic building block of life

Starting with tryptophan, CrTdc forms tryptamine via decarboxylation. Then PsiH, which is activated by CPR, adds a hydroxyl group to tryptamine’s benzene ring. PsiH is of a breed of enzyme known as monooxygenase cytochrome P450, which are notorious within synthetic biology groups for being difficult to functionally express in non-native cell types because they require a cytochrome P450 reductase, in this case, CPR. PsiH's hydroxylation of tryptamine, produces 4-Hydroxytryptamine. This is considered the committing step of the pathway, once 4-Hydroxytryptamine is made, there are likely no other metabolic pathways it can proceed into. Tryptophan and tryptamine can be used to make many other metabolites, but 4-Hydroxytryptamine can only be funneled into the psilocybin pathway. PsiK phosphorylates the hydroxyl group to create Norbaeocystine, which is then acted on twice by PsiM to iteratively transfer methyl groups to the amine, producing Baeocystin, then Psilocybin.

Academic Literature on Elucidating the Enzymatic Pathway:

Fricke et al. 2017 elucidated most of the biosynthetic pathway of psilocybin from two species of psychedelic mushrooms: P. cubensis and P. cyanescens.   

Milne et al. 2020 found a novel P450 reductase native to P. cubensis. 

Below is a bit more history on humanity's attempts to synthesize psilocybin: