Synthesis and evaluation of bioorthogonal pantetheine analogues for in vivo protein modification

J Am Chem Soc. 2006 Sep 20;128(37):12174-84. doi: 10.1021/ja063217n.

Abstract

In vivo carrier protein tagging has recently become an attractive target for the site-specific modification of fusion systems and new approaches to natural product proteomics. A detailed study of pantetheine analogues was performed in order to identify suitable partners for covalent protein labeling inside living cells. A rapid synthesis of pantothenamide analogues was developed and used to produce a panel which was evaluated for in vitro and in vivo protein labeling. Kinetic comparisons allowed the construction of a structure-activity relationship to pinpoint the linker, dye, and bioorthogonal reporter of choice for carrier protein labeling. Finally bioorthogonal pantetheine analogues were shown to target carrier proteins with high specificity in vivo and undergo chemoselective ligation to reporters in crude cell lysate. The methods demonstrated here allow carrier proteins to be visualized and isolated for the first time without the need for antibody techniques and set the stage for the future use of carrier protein fusions in chemical biology.

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

  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Coenzyme A / chemistry
  • Coenzyme A / metabolism
  • Escherichia coli / metabolism
  • Kinetics
  • Pantetheine / analogs & derivatives*
  • Pantetheine / chemical synthesis
  • Pantetheine / chemistry
  • Pantetheine / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity
  • Transferases (Other Substituted Phosphate Groups) / chemistry
  • Transferases (Other Substituted Phosphate Groups) / metabolism

Substances

  • Bacterial Proteins
  • Carrier Proteins
  • phosphopantetheinyl transferase
  • Pantetheine
  • Transferases (Other Substituted Phosphate Groups)
  • Coenzyme A