Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 61, Issue 41, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202208746
Keywords
Biocatalysis; Late-Stage Methylation; Methyl Toluenesulfonate; Methyltransferase; S-Adenosylmethionine
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Funding
- Camille and Henry Dreyfus Foundation
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Late-stage methylation is a crucial technology in pharmaceutical compound development. Methyltransferase biocatalysis offers a powerful option for inserting methyl groups into complex molecules with high selectivity. However, large-scale application of methyltransferases is hindered by the expensive S-adenosylmethionine (SAM) co-substrate and the handling of volatile electrophiles like methyl iodide (MeI). To overcome these challenges, researchers have developed an enzyme-catalyzed process using methyl toluene sulfonate for SAM regeneration.
Late-stage methylation is a key technology in the development of pharmaceutical compounds. Methyltransferase biocatalysis may provide powerful options to insert methyl groups into complex molecules with high regio- and chemoselectivity. The challenge of a large-scale application of methyltransferases is their dependence on S-adenosylmethionine (SAM) as a stoichiometric, and thus exceedingly expensive co-substrate. As a solution to this problem, we and others have explored the use of methyl halides as reagents for the in situ regeneration of SAM. However, the need to handle volatile electrophiles, such as methyl iodide (MeI), may also hamper applications at scale. As a more practical solution, we have now developed an enzyme-catalyzed process for the regeneration of SAM with methyl toluene sulfonate. Herein, we describe enzymes from the thiopurine methyltransferase family that accept sulfate- and sulfonate-based methyl donors to convert S-adenosylhomocysteine into SAM with efficiencies that rival MeI-based reactions.
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