Minimalist enzymes designed to catalyze model reactions provide useful starting points for creating catalysts for practically important chemical transformations. We have shown that Kemp eliminases of the AlleyCat family facilitate conversion of leflunomide (an immunosuppressor pro‐drug) to its active form teriflunomide with outstanding rate enhancement (nearly four orders of magnitude) and catalytic proficiency (more than seven orders of magnitude) without any additional optimization. This remarkable activity is achieved by properly positioning the substrate in close proximity to the catalytic glutamate with very high pKa.
The Front Cover picture shows that AlleyCat2, a member of the AlleyCat family of allosterically regulated Kemp eliminases, is capable of binding leflunomide, an immunosuppressant drug, and converting it into teriflunomide, its active form, with remarkable efficiency. In their Communication, E. A. Caselle, J. H. Yoon et al. show that small libraries of designed catalysts provide fertile ground for discovering new reactivities. AlleyCat2 relies on a high pKa of the active base and proper positioning of the substrate in the hydrophobic cleft of the enzyme to promote catalysis. This work also demonstrates that using pH rate profiles to determine the pKa of the active residue can be quite misleading and NMR studies that can probe specific atoms directly provide invaluable mechanistic information. More information can be found in the Communication by E. A. Caselle, J. H. Yoon et al. on page 1425 in Issue 5, 2019 (DOI: 10.1002/cctc.201801994).
The front cover artwork for Issue 05/2019 is provided by the Korendoych and the Makhlynets Labs at Syracuse University (USA) in collaboration with the VIB Centre for Structural Biology (Belgium), College of Charleston (USA) and Kyiv National University (Ukraine). The image shows AlleyCat2, a minimalist allosterically regulated Kemp eliminase, efficiently promoting ring opening of leflunomide, an immunosuppresant. Small libraries of designed catalysts provide fertile ground for discovering new reactivities. See the Communication itself at https://doi.org/10.1002/cctc.201801994.
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