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A de novo Enzyme for the Morita-Baylis-Hillman Reaction BH32.12
Structural highlights
Publication Abstract from PubMedThe combination of computational design and directed evolution could offer a general strategy to create enzymes with new functions. So far, this approach has delivered enzymes for a handful of model reactions. Here we show that new catalytic mechanisms can be engineered into proteins to accelerate more challenging chemical transformations. Evolutionary optimization of a primitive design afforded an efficient and enantioselective enzyme (BH32.14) for the Morita-Baylis-Hillman (MBH) reaction. BH32.14 is suitable for preparative-scale transformations, accepts a broad range of aldehyde and enone coupling partners and is able to promote selective monofunctionalizations of dialdehydes. Crystallographic, biochemical and computational studies reveal that BH32.14 operates via a sophisticated catalytic mechanism comprising a His23 nucleophile paired with a judiciously positioned Arg124. This catalytic arginine shuttles between conformational states to stabilize multiple oxyanion intermediates and serves as a genetically encoded surrogate of privileged bidentate hydrogen-bonding catalysts (for example, thioureas). This study demonstrates that elaborate catalytic devices can be built from scratch to promote demanding multi-step processes not observed in nature. Engineering an efficient and enantioselective enzyme for the Morita-Baylis-Hillman reaction.,Crawshaw R, Crossley AE, Johannissen L, Burke AJ, Hay S, Levy C, Baker D, Lovelock SL, Green AP Nat Chem. 2021 Dec 16. pii: 10.1038/s41557-021-00833-9. doi:, 10.1038/s41557-021-00833-9. PMID:34916595[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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