Inverted binding of non-natural substrates in strictosidine synthase leads to a switch of stereochemical outcome in enzyme-catalyzed Pictet-Spengler reactions

Elisabeth Eger, Simon Adam, Mahima Sharma, Song Yang, Willem Breukelaar, Gideon James Grogan, Ken Houk, Wolfgang Kroutil

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The Pictet-Spengler reaction is a valuable route to 1,2,3,4-tetrahydro-Β-carboline (THBC) and isoquinoline scaffolds
found in many important pharmaceuticals. Strictosidine synthase (STR), catalyzes the Pictet-Spengler condensation of tryptamine
and the aldehyde secologanin to give (S)-strictosidine as a key intermediate in indole alkaloid biosynthesis. STRs also accept shortchain
aliphatic aldehydes to give enantioenriched alkaloid products with up to 99% e.e. STRs are thus valuable asymmetric organocatalysts
for applications in organic synthesis. The STR catalysis of reactions of small aldehydes gives an unexpected switch in
stereopreference, leading to formation of the (R)-products. Here we report a rationale for the formation of the (R)-configured products
by the STR enzyme from Ophiorrhiza pumila (OpSTR) using a combination of X-ray crystallography, mutational and molecular
dynamics (MD) studies. We discovered that short chain aldehydes bind in an inverted fashion compared to secologanin leading to
the inverted stereopreference for the observed (R)-product in those cases. The study demonstrates that the same catalyst can have two
different productive binding modes for one substrate – but give different absolute configuration of the products by binding the aldehyde
substrate differently. These results will guide future engineering of STRs and related enzymes for biocatalytic applications.
Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalJournal of the American Chemical Society
Early online date7 Jan 2020
Publication statusPublished - 15 Jan 2020

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