Genetically programmed chiral organoborane synthesis

Nature. 2017 Dec 7;552(7683):132-136. doi: 10.1038/nature24996. Epub 2017 Nov 29.

Abstract

Recent advances in enzyme engineering and design have expanded nature's catalytic repertoire to functions that are new to biology. However, only a subset of these engineered enzymes can function in living systems. Finding enzymatic pathways that form chemical bonds that are not found in biology is particularly difficult in the cellular environment, as this depends on the discovery not only of new enzyme activities, but also of reagents that are both sufficiently reactive for the desired transformation and stable in vivo. Here we report the discovery, evolution and generalization of a fully genetically encoded platform for producing chiral organoboranes in bacteria. Escherichia coli cells harbouring wild-type cytochrome c from Rhodothermus marinus (Rma cyt c) were found to form carbon-boron bonds in the presence of borane-Lewis base complexes, through carbene insertion into boron-hydrogen bonds. Directed evolution of Rma cyt c in the bacterial catalyst provided access to 16 novel chiral organoboranes. The catalyst is suitable for gram-scale biosynthesis, providing up to 15,300 turnovers, a turnover frequency of 6,100 h-1, a 99:1 enantiomeric ratio and 100% chemoselectivity. The enantiopreference of the biocatalyst could also be tuned to provide either enantiomer of the organoborane products. Evolved in the context of whole-cell catalysts, the proteins were more active in the whole-cell system than in purified forms. This study establishes a DNA-encoded and readily engineered bacterial platform for borylation; engineering can be accomplished at a pace that rivals the development of chemical synthetic methods, with the ability to achieve turnovers that are two orders of magnitude (over 400-fold) greater than those of known chiral catalysts for the same class of transformation. This tunable method for manipulating boron in cells could expand the scope of boron chemistry in living systems.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Biocatalysis
  • Boron / chemistry*
  • Boron / metabolism
  • Cytochromes c / genetics*
  • Cytochromes c / metabolism*
  • Directed Molecular Evolution*
  • Escherichia coli / genetics
  • Escherichia coli / metabolism*
  • Hydrogen / chemistry*
  • Hydrogen / metabolism
  • Hydrogen Bonding
  • Metabolic Engineering*
  • Metabolic Networks and Pathways / genetics
  • Molecular Structure
  • Rhodothermus / enzymology*
  • Rhodothermus / genetics
  • Stereoisomerism

Substances

  • Hydrogen
  • Cytochromes c
  • Boron