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Noncanonical Heme Ligands Steer Carbene Transfer Reactivity in an Artificial Metalloenzyme **
Author(s) -
Pott Moritz,
Tinzl Matthias,
Hayashi Takahiro,
Ota Yusuke,
Dunkelmann Daniel,
Mittl Peer R. E.,
Hilvert Donald
Publication year - 2021
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202103437
Subject(s) - chemistry , histidine , myoglobin , metalloprotein , carbene , heme , cyclopropanation , stereochemistry , enzyme , heme a , reactivity (psychology) , redox , combinatorial chemistry , alanine , biochemistry , amino acid , catalysis , organic chemistry , medicine , alternative medicine , pathology
Abstract Changing the primary metal coordination sphere is a powerful strategy for tuning metalloprotein properties. Here we used amber stop codon suppression with engineered pyrrolysyl‐tRNA synthetases, including two newly evolved enzymes, to replace the proximal histidine in myoglobin with N δ ‐methylhistidine, 5‐thiazoylalanine, 4‐thiazoylalanine and 3‐(3‐thienyl)alanine. In addition to tuning the heme redox potential over a >200 mV range, these noncanonical ligands modulate the protein's carbene transfer activity with ethyl diazoacetate. Variants with increased reduction potential proved superior for cyclopropanation and N–H insertion, whereas variants with reduced E o values gave higher S–H insertion activity. Given the functional importance of histidine in many enzymes, these genetically encoded analogues could be valuable tools for probing mechanism and enabling new chemistries.

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