Two tricks in one bundle: helix-turn-helix gains enzymatic activity

Nucleic Acids Res. 2000 Jun 1;28(11):2229-33. doi: 10.1093/nar/28.11.2229.


Many examples of enzymes that have lost their catalytic activity and perform other biological functions are known. The opposite situation is rare. A previously unnoticed structural similarity between the lambda integrase family (Int) proteins and the AraC family of transcriptional activators implies that the Int family evolved by duplication of an ancient DNA-binding homeodomain-like module, which acquired enzymatic activity. The two helix-turn-helix (HTH) motifs in Int proteins incorporate catalytic residues and participate in DNA binding. The active site of Int proteins, which include the type IB topoisomerases, is formed at the domain interface and the catalytic tyrosine residue is located in the second helix of the C-terminal HTH motif. Structural analysis of other 'tyrosine' DNA-breaking/rejoining enzymes with similar enzyme mechanisms, namely prokaryotic topoisomerase I, topoisomerase II and archaeal topoisomerase VI, reveals that the catalytic tyrosine is placed in a HTH domain as well. Surprisingly, the location of this tyrosine residue in the structure is not conserved, suggesting independent, parallel evolution leading to the same catalytic function by homologous HTH domains. The 'tyrosine' recombinases give a rare example of enzymes that evolved from ancient DNA-binding modules and present a unique case for homologous enzymatic domains with similar catalytic mechanisms but different locations of catalytic residues, which are placed at non-homologous sites.

MeSH terms

  • Amino Acid Sequence
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacteriophages
  • Binding Sites
  • DNA Nucleotidyltransferases / chemistry
  • DNA Nucleotidyltransferases / genetics
  • DNA Topoisomerases, Type I / chemistry
  • DNA Topoisomerases, Type I / genetics
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • Escherichia coli
  • Evolution, Molecular
  • Fungal Proteins / chemistry
  • Fungal Proteins / genetics
  • Helix-Turn-Helix Motifs / genetics*
  • Integrases / chemistry
  • Integrases / genetics*
  • Models, Molecular
  • Molecular Sequence Data
  • Recombinases
  • Trans-Activators / chemistry
  • Trans-Activators / genetics
  • Tyrosine / genetics
  • Viral Proteins / chemistry
  • Viral Proteins / genetics


  • Bacterial Proteins
  • DNA-Binding Proteins
  • Fungal Proteins
  • Recombinases
  • Trans-Activators
  • Viral Proteins
  • Tyrosine
  • DNA Nucleotidyltransferases
  • Integrases
  • integron integrase IntI1
  • DNA Topoisomerases, Type I