Product-assisted catalysis in base-excision DNA repair.
Most spontaneous damage to bases in DNA is corrected through the action of the base-excision DNA repair pathway. Base excision repair is initiated by DNA glycosylases, lesion-specific enzymes that intercept aberrant bases in DNA and catalyze their excision. How such proteins accomplish the feat of catalyzing no fewer than five sequential reaction steps using a single active site has been unknown. To help answer this, we report the structure of a trapped catalytic intermediate in DNA repair by human 8-oxoguanine DNA glycosylase. This structure and supporting biochemical results reveal that the enzyme sequesters the excised lesion base and exploits it as a cofactor to participate in catalysis. To our knowledge, the present example represents the first documented case of product-assisted catalysis in an enzyme-catalyzed reaction.
Fromme
J Christopher
JC
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Bruner
Steven D
SD
Yang
Wei
W
Karplus
Martin
M
Verdine
Gregory L
GL
D019943:Amino Acid Substitution; D020029:Base Pairing; D001894:Borohydrides / Q000737:chemistry; D002384:Catalysis; D004260:DNA Repair / Q000502:physiology*; D043382:DNA-Formamidopyrimidine Glycosylase; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D021621:Imaging, Three-Dimensional; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009699:N-Glycosyl Hydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D012545:Schiff Bases / Q000737:chemistry / Q000378:metabolism
D001894:Borohydrides; D012545:Schiff Bases; C024829:8-hydroxyguanine; D006147:Guanine; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; D008239:Lysine