Tryptophan synthase, an allosteric molecular factory.

Long-range side-chain-main-chain interactions play crucial roles in stabilizing the (betaalpha)8 barrel motif of the alpha subunit of tryptophan synthase.

DNA sequence of the tryptophan synthase genes of Pseudomonas putida.

Mechanism of mutual activation of the tryptophan synthase alpha and beta subunits.

Tryptophan synthase: the workings of a channeling nanomachine.

Time-resolved fluorescence anisotropy study of the refolding reaction of the alpha-subunit of tryptophan synthase reveals nonmonotonic behavior of the rotational correlation time.

A convenient enzymatic synthesis of L-halotryptophans.

Folding mechanism of the alpha-subunit of tryptophan synthase, an alpha/beta barrel protein: global analysis highlights the interconversion of multiple native, intermediate, and unfolded forms through parallel channels.

Kinetic characterization of channel impaired mutants of tryptophan synthase.

The role of the TRP1 gene in yeast tryptophan biosynthesis

Medicinal chemist of the University of Minnesota, Twin Cities, praises Hoffmeister and his coworkers for their painstaking efforts to elucidate the biosynthesis of psilocybin. “Our knowledge of the biosynthesis of fungal natural products has lagged behind our understanding of the corresponding bacterial biosynthetic pathways owing to a number of unique challenges,” Aldrich says. For instance, the genomes of fungi are more complex than bacteria, many fungi are still not amenable to genetic manipulation, and cultivating fungi to produce sufficient amounts of desired metabolites is not always straightforward. “The new work lays the foundation for developing a fermentation process for production of this powerful psychedelic fungal drug, which has a fascinating history and pharmacology,” Aldrich adds.

Terminal reactions in tryptophan biosynthesis in yeast

The shikimate pathway consists of seven enzymatic reactions whose end product chorismate is the precursor for the synthesis of the aromatic amino acids Phe, Tyr and Trp. In fungi and plants, chorismate is a precursor for many specialised metabolites (i.e. secondary metabolites) that play an important role in the plant's interaction with its environment. The shikimate pathway and aromatic amino acid biosynthesis have been extensively studied in a variety of microorganisms, fungi and plants. Furthermore, the dual involvement of the shikimate and aromatic amino acid biosynthesis pathways in central and specialised metabolism still raises major questions regarding the genes and enzymes involved, and their control, their evolutionary origins and coordinated regulation with genes of associated pathways in response to altered environmental conditions and diverse developmental programs.

Cooperative fluctuations and subunit communication in tryptophan synthase.

The beta subunit of tryptophan synthase.

Graindorge M, Giustini C, Jacomin AC et al. (2010) Identification of a plant gene encoding glutamate/aspartate‐prephenate aminotransferase: the last homeless enzyme of aromatic amino acids biosynthesis. FEBS Letters 584(20): 4357–4360.

A gene encoding the tryptophan synthase beta subunit of Arabidopsis thaliana.

Inhibition of tryptophan synthase by (1-fluorovinyl)glycine.

Cho M, Corea O, Yang H et al. (2007) Phenylalanine biosynthesis in Arabidopsis thaliana identification and characterization of arogenate dehydratases. Journal of Biological Chemistry 282(42): 30827–30835.

Regulation of enzyme synthesis in the tryptophan pathway of Acinetobacter calcoaceticus.

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During their study, Hoffmeister and coworkers sequenced the genomes of two mushroom species to identify the genes that govern fungal enzymatic production of psilocybin. They further used engineered bacteria and fungi to confirm the gene activity and exact order of synthetic steps. This process includes a newly discovered enzyme that decarboxylates tryptophan, an enzyme that adds a hydroxyl group, an enzyme that catalyzes phosphorylation, and an enzyme that mediates two sequential amine methylation steps. With that knowledge in hand, the team designed a one-pot reaction using three of the enzymes to prepare psilocybin from 4-hydroxy--tryptophan.