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Inverted Binding of Non-natural Substrates in Strictosidine Synthase Leads to a Switch of Stereochemical Outcome in Enzyme-Catalyzed Pictet-Spengler Reactions.

<div class='caption-title'>Results published previously.20b</div>
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Eger E, Simon A, Sharma M, Yang S, Breukelaar WB, Grogan G, Houk KN, Kroutil W
OpenAccess logo J Am Chem Soc 142 792-800 (2020)
Related entries: 6s5j, 6s5m, 6s5q

Cited: 10 times
EuropePMC logo PMID: 31909617

Abstract

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 short-chain aliphatic aldehydes to give enantioenriched alkaloid products with up to 99% ee 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.

Reviews citing this publication (4)

  1. Recent trends in biocatalysis. Yi D, Bayer T, Badenhorst CPS, Wu S, Doerr M, Höhne M, Bornscheuer UT. Chem Soc Rev 50 8003-8049 (2021)
  2. Enzymatic Late-Stage Modifications: Better Late Than Never. Romero E, Jones BS, Hogg BN, Rué Casamajo A, Hayes MA, Flitsch SL, Turner NJ, Schnepel C. Angew Chem Int Ed Engl 60 16824-16855 (2021)
  3. The role of biocatalysis in the asymmetric synthesis of alkaloids - an update. Cigan E, Eggbauer B, Schrittwieser JH, Kroutil W. RSC Adv 11 28223-28270 (2021)
  4. New Trends and Future Opportunities in the Enzymatic Formation of C-C, C-N, and C-O bonds. Sangster JJ, Marshall JR, Turner NJ, Mangas-Sanchez J. Chembiochem 23 e202100464 (2022)

Articles citing this publication (6)

  1. The AutoDock suite at 30. Goodsell DS, Sanner MF, Olson AJ, Forli S. Protein Sci 30 31-43 (2021)
  2. Asymmetric Biocatalytic Synthesis of 1-Aryltetrahydro-β-carbolines Enabled by "Substrate Walking". Eger E, Schrittwieser JH, Wetzl D, Iding H, Kuhn B, Kroutil W. Chemistry 26 16281-16285 (2020)
  3. Single step syntheses of (1S)-aryl-tetrahydroisoquinolines by norcoclaurine synthases. Roddan R, Sula A, Méndez-Sánchez D, Subrizi F, Lichman BR, Broomfield J, Richter M, Andexer JN, Ward JM, Keep NH, Hailes HC. Commun Chem 3 170 (2020)
  4. Directed Biosynthesis of New to Nature Alkaloids in a Heterologous Nicotiana benthamiana Expression Host. Boccia M, Grzech D, Lopes AA, O'Connor SE, Caputi L. Front Plant Sci 13 919443 (2022)
  5. Uncovering the Mechanism of Azepino-Indole Skeleton Formation via Pictet-Spengler Reaction by Strictosidine Synthase: A Quantum Chemical Investigation. Mou M, Zhang C, Zhang S, Chen F, Su H, Sheng X. ChemistryOpen 12 e202300043 (2023)
  6. Elucidation of the 1-phenethylisoquinoline pathway from an endemic conifer Cephalotaxus hainanensis. Qiao F, He Y, Zhang Y, Jiang X, Cong H, Wang Z, Sun H, Xiao Y, Zhao Y, Nick P. Proc Natl Acad Sci U S A 120 e2209339120 (2023)


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