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Noncanonical Heme Ligands Steer Carbene Transfer Reactivity in an Artificial Metalloenzyme*.

Moritz PottMatthias TinzlTakahiro HayashiYusuke OtaDaniel L DunkelmannPeer R E MittlDonald Hilvert
Published in: Angewandte Chemie (International ed. in English) (2021)
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 Nδ -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 Eo 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.
Keyphrases
  • copy number
  • human health
  • electron transfer
  • risk assessment
  • molecular dynamics simulations
  • ionic liquid
  • single molecule
  • binding protein
  • climate change
  • small molecule
  • protein protein
  • dna methylation