Biosynthetic Pathway of Ergothioneine

Ergothioneine (EGT) is a well-studied example of a natural product synthesized by certain fungi, mycobacteria, and cyanobacteria. Ergothioneine is a sulfur-containing derivative of the amino acid histidine and has potent antioxidant properties.

Overview of Ergothioneine Biosynthesis

Key features:

• Starts from L-histidine

• Involves methylation and sulfur transfer

• Key enzymes are typically EgtA to EgtE (in Mycobacterium smegmatis) or slightly different in fungi

Bacterial Pathway (e.g., Mycobacterium smegmatis)

1. L-Histidine → Hercynine

• Enzyme: EgtD

• Reaction: Methylation of L-histidine using S-adenosylmethionine (SAM) as the methyl donor

• Product: Hercynine (trimethylated histidine)

2. Hercynine + γ-glutamylcysteine → S-(hercyn-2-yl)-γ-glutamylcysteine sulfoxide

• Enzyme: EgtB

• Reaction: Sulfoxide synthase reaction introducing sulfur via oxidative coupling

• Note: EgtB uses molecular oxygen and non-heme iron

3. S-(hercyn-2-yl)-γ-glutamylcysteine sulfoxide → Hercynylcysteine sulfoxide

• Enzyme: EgtC

• Reaction: Removal of the γ-glutamyl group

• Product: Hercynylcysteine sulfoxide

4. Hercynylcysteine sulfoxide → Ergothioneine

• Enzyme: EgtE

• Reaction: PLP-dependent C–S bond rearrangement

• Product: Ergothioneine

Fungal Pathway (e.g., Neurospora crassa, Aspergillus spp.)

In fungi, the pathway is similar but can use slightly different enzyme names and mechanisms:

• Fungi often use EGT1, a bifunctional enzyme with methyltransferase and sulfoxide synthase activity (combining EgtD and EgtB functions).

• Some also use EGT2 for the conversion of hercynylcysteine sulfoxide to Ergothioneine.

Summary of Key Enzymes

Would you like a diagram of the pathway or an explanation of the chemical structures involved?