N-terminal modifications of cellular proteins: The enzymes involved, their substrate specificities and biological effects

Proteomics. 2015 Jul;15(14):2385-401. doi: 10.1002/pmic.201400619. Epub 2015 Jun 16.


The vast majority of eukaryotic proteins are N-terminally modified by one or more processing enzymes. Enzymes acting on the very first amino acid of a polypeptide include different peptidases, transferases, and ligases. Methionine aminopeptidases excise the initiator methionine leaving the nascent polypeptide with a newly exposed amino acid that may be further modified. N-terminal acetyl-, methyl-, myristoyl-, and palmitoyltransferases may attach an acetyl, methyl, myristoyl, or palmitoyl group, respectively, to the α-amino group of the target protein N-terminus. With the action of ubiquitin ligases, one or several ubiquitin molecules are transferred, and hence, constitute the N-terminal modification. Modifications at protein N-termini represent an important contribution to proteomic diversity and complexity, and are essential for protein regulation and cellular signaling. Consequently, dysregulation of the N-terminal modifying enzymes is implicated in human diseases. We here review the different protein N-terminal modifications occurring co- or post-translationally with emphasis on the responsible enzymes and their substrate specificities.

Keywords: Acetylation; Cell biology; N-terminal; Protein modification; Substrate specificity; α-amino group.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Acetylation
  • Animals
  • Humans
  • Protein Processing, Post-Translational*
  • Proteins / chemistry*
  • Proteins / metabolism*
  • Proteomics
  • Substrate Specificity


  • Proteins