tRNA(His) guanylyltransferase (THG1), a unique 3'-5' nucleotidyl transferase, shares unexpected structural homology with canonical 5'-3' DNA polymerases

Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20305-10. doi: 10.1073/pnas.1010436107. Epub 2010 Nov 8.


All known DNA and RNA polymerases catalyze the formation of phosphodiester bonds in a 5' to 3' direction, suggesting this property is a fundamental feature of maintaining and dispersing genetic information. The tRNA(His) guanylyltransferase (Thg1) is a member of a unique enzyme family whose members catalyze an unprecedented reaction in biology: 3'-5' addition of nucleotides to nucleic acid substrates. The 2.3-Å crystal structure of human THG1 (hTHG1) reported here shows that, despite the lack of sequence similarity, hTHG1 shares unexpected structural homology with canonical 5'-3' DNA polymerases and adenylyl/guanylyl cyclases, two enzyme families known to use a two-metal-ion mechanism for catalysis. The ability of the same structural architecture to catalyze both 5'-3' and 3'-5' reactions raises important questions concerning selection of the 5'-3' mechanism during the evolution of nucleotide polymerases.

Publication types

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

MeSH terms

  • Crystallography
  • Evolution, Molecular
  • Guanosine / metabolism*
  • Humans
  • Models, Molecular*
  • Molecular Structure
  • Nucleotidyltransferases / chemistry*
  • Nucleotidyltransferases / metabolism
  • RNA, Transfer, His / metabolism*
  • RNA-Directed DNA Polymerase / chemistry*
  • RNA-Directed DNA Polymerase / metabolism


  • RNA, Transfer, His
  • Guanosine
  • Nucleotidyltransferases
  • tRNA guanylyltransferase
  • RNA-Directed DNA Polymerase

Associated data

  • PDB/3OTB
  • PDB/3OTC
  • PDB/3OTD
  • PDB/3OTE