Discovery of a pathway for terminal-alkyne amino acid biosynthesis

Nature. 2019 Mar;567(7748):420-424. doi: 10.1038/s41586-019-1020-y. Epub 2019 Mar 13.

Abstract

Living systems can generate an enormous range of cellular functions, from mechanical infrastructure and signalling networks to enzymatic catalysis and information storage, using a notably limited set of chemical functional groups. This observation is especially notable when compared to the breadth of functional groups used as the basis for similar functions in synthetically derived small molecules and materials. The relatively small cross-section between biological and synthetic reactivity space forms the foundation for the development of bioorthogonal chemistry, in which the absence of a pair of reactive functional groups within the cell allows for a selective in situ reaction1-4. However, biologically 'rare' functional groups, such as the fluoro5, chloro6,7, bromo7,8, phosphonate9, enediyne10,11, cyano12, diazo13, alkene14 and alkyne15-17 groups, continue to be discovered in natural products made by plants, fungi and microorganisms, which offers a potential route to genetically encode the endogenous biosynthesis of bioorthogonal reagents within living organisms. In particular, the terminal alkyne has found broad utility via the Cu(I)-catalysed azide-alkyne cycloaddition 'click' reaction18. Here we report the discovery and characterization of a unique pathway to produce a terminal alkyne-containing amino acid in the bacterium Streptomyces cattleya. We found that L-lysine undergoes an unexpected reaction sequence that includes halogenation, oxidative C-C bond cleavage and triple bond formation through a putative allene intermediate. This pathway offers the potential for de novo cellular production of halo-, alkene- and alkyne-labelled proteins and natural products from glucose for a variety of downstream applications.

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

  • Alkadienes / chemistry
  • Alkadienes / metabolism
  • Alkenes / chemistry
  • Alkenes / metabolism
  • Alkynes / chemistry*
  • Alkynes / metabolism*
  • Amino Acids / biosynthesis*
  • Amino Acids / chemistry*
  • Bacterial Proteins / metabolism
  • Biosynthetic Pathways* / genetics
  • Carbon / chemistry
  • Carbon / metabolism
  • Glucose / chemistry
  • Glucose / metabolism
  • Halogenation
  • Lysine / chemistry
  • Lysine / metabolism
  • Multigene Family / genetics
  • Serine / analogs & derivatives
  • Serine / biosynthesis
  • Serine / chemistry
  • Streptomyces / genetics
  • Streptomyces / metabolism*

Substances

  • Alkadienes
  • Alkenes
  • Alkynes
  • Amino Acids
  • Bacterial Proteins
  • Serine
  • propadiene
  • 3-ethynylserine
  • Carbon
  • Glucose
  • Lysine