Aminoacyl-transferases and the N-end rule pathway of prokaryotic/eukaryotic specificity in a human pathogen

Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3078-83. doi: 10.1073/pnas.0511224103. Epub 2006 Feb 21.


The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. Primary destabilizing N-terminal residues (Nd(p)) are recognized directly by the targeting machinery. The recognition of secondary destabilizing N-terminal residues (Nd(s)) is preceded by conjugation of an Nd(p) residue to Nd(s) of a polypeptide substrate. In eukaryotes, ATE1-encoded arginyl-transferases (R(D,E,C*)-transferases) conjugate Arg (R), an Nd(p) residue, to Nd(s) residues Asp (D), Glu (E), or oxidized Cys residue (C*). Ubiquitin ligases recognize the N-terminal Arg of a substrate and target the (ubiquitylated) substrate to the proteasome. In prokaryotes such as Escherichia coli, Nd(p) residues Leu (L) or Phe (F) are conjugated, by the aat-encoded Leu/Phe-transferase (L/F(K,R)-transferase), to N-terminal Arg or Lys, which are Nd(s) in prokaryotes but Nd(p) in eukaryotes. In prokaryotes, substrates bearing the Nd(p) residues Leu, Phe, Trp, or Tyr are degraded by the proteasome-like ClpAP protease. Despite enzymological similarities between eukaryotic R(D,E,C*)-transferases and prokaryotic L/F(K,R)-transferases, there is no significant sequelogy (sequence similarity) between them. We identified an aminoacyl-transferase, termed Bpt, in the human pathogen Vibrio vulnificus. Although it is a sequelog of eukaryotic R(D,E,C*)-transferases, this prokaryotic transferase exhibits a "hybrid" specificity, conjugating Nd(p) Leu to Nd(s) Asp or Glu. Another aminoacyl-transferase, termed ATEL1, of the eukaryotic pathogen Plasmodium falciparum, is a sequelog of prokaryotic L/F(K,R)-transferases (Aat), but has the specificity of eukaryotic R(D,E,C*)-transferases (ATE1). Phylogenetic analysis suggests that the substrate specificity of R-transferases arose by two distinct routes during the evolution of eukaryotes.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Aminoacyltransferases / chemistry
  • Aminoacyltransferases / genetics
  • Aminoacyltransferases / metabolism*
  • Conserved Sequence
  • Cysteine / genetics
  • Cysteine / metabolism
  • Eukaryotic Cells / enzymology*
  • Evolution, Molecular
  • Half-Life
  • Humans
  • Malaria / enzymology
  • Models, Biological
  • Phylogeny
  • Prokaryotic Cells / enzymology*
  • Tyrosine / genetics
  • Tyrosine / metabolism
  • Vibrio vulnificus / enzymology
  • Vibrio vulnificus / genetics


  • Tyrosine
  • Aminoacyltransferases
  • Cysteine