tRNA(His) guanylyltransferase (THG1), a unique 3'-5' nucleotidyl transferase, shares unexpected structural homology with canonical 5'-3' DNA polymerases.
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.
Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont 05405, USA.
Samantha J
SJ
Hyde
Brian E
BE
Eckenroth
Brian A
BA
Smith
William A
WA
Eberley
Nicholas H
NH
Heintz
Jane E
JE
Jackman
Sylvie
S
Doublié
D003461:Crystallography; D019143:Evolution, Molecular; D006151:Guanosine / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009713:Nucleotidyltransferases / Q000737:chemistry* / Q000378:metabolism; D012354:RNA, Transfer, His / Q000378:metabolism*; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry* / Q000378:metabolism
D012354:RNA, Transfer, His; D006151:Guanosine; D009713:Nucleotidyltransferases; C065307:tRNA guanylyltransferase; D012194:RNA-Directed DNA Polymerase