An Engineered Tryptophan Synthase Opens New Enzymatic Pathways to β‐Methyltryptophan and Derivatives. (20th January 2017)

• Record Type: Journal Article
• Authors: Francis, Daniel; Winn, Michael; Latham, Jonathan; Greaney, Michael F.; Micklefield, Jason
• Is Part Of: Chembiochem. Volume 18:Number 4(2017)
• Page Start: 382
• Page End: 386
• Publication Date: 2017-01-20
• Subjects: biocatalysis -- enzyme cascades -- methylamino acids -- peptidomimetics -- tryptophan synthase; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201600471
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: β‐Methyltryptophans (β‐mTrp) are precursors in the biosynthesis of bioactive natural products and are used in the synthesis of peptidomimetic‐based therapeutics. Currently β‐mTrp is produced by inefficient multistep synthetic methods. Here we demonstrate how an engineered variant of tryptophan synthase from Salmonella ( St TrpS) can catalyse the efficient condensation ofl ‐threonine and various indoles to generate β‐mTrp and derivatives in a single step. Althoughl ‐serine is the natural substrate for TrpS, targeted mutagenesis of the St TrpS active site provided a variant (βL166V) that can better accommodatel ‐Thr as a substrate. The condensation ofl ‐Thr and indole proceeds with retention of configuration at both α‐ and β‐positions to give (2 S, 3 S )‐β‐mTrp. The integration of St TrpS (βL166V) withl ‐amino acid oxidase, halogenase enzymes and palladium chemocatalysts provides access to furtherd ‐configured and regioselectively halogenated or arylated β‐mTrp derivatives. Abstract : It's getting to Me : A mutant tryptophan synthase ( St TrpS) catalyses the condensation of 2‐, 4‐, 6‐ and 7‐substituted indoles with threonine to give (2 S, 3 S )‐β‐methyltryptophans (β‐mTrp), which are important building blocks in drug synthesis. Addition ofl ‐amino acid oxidase (LAAO) gives (2 R, 3 S )‐β‐mTrp. Halogenase (Hal) enzymes also provide halogenated β‐mTrp derivatives that can be arylated in a one‐pot chemo‐biotransformation.