title: Catalysts of DNA Strand Cleavage at Apurinic/Apyrimidinic Sites.
abstract: Apurinic/apyrimidinic (AP) sites are constantly formed in cellular DNA due to instability of the glycosidic bond, particularly at purines and various oxidized, alkylated, or otherwise damaged nucleobases. AP sites are also generated by DNA glycosylases that initiate DNA base excision repair. These lesions represent a significant block to DNA replication and are extremely mutagenic. Some DNA glycosylases possess AP lyase activities that nick the DNA strand at the deoxyribose moiety via a β- or β,δ-elimination reaction. Various amines can incise AP sites via a similar mechanism, but this non-enzymatic cleavage typically requires high reagent concentrations. Herein, we describe a new class of small molecules that function at low micromolar concentrations as both β- and β,δ-elimination catalysts at AP sites. Structure-activity relationships have established several characteristics that appear to be necessary for the formation of an iminium ion intermediate that self-catalyzes the elimination at the deoxyribose ring.
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health &Science University, Portland, Oregon 97239, United States.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Minko
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health &Science University, Portland, Oregon 97239, United States.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Jacobs
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.
authors.forename: Arnie R
authors.initials: AR
authors.lastname: de Leon
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.
authors.forename: Francesca
authors.initials: F
authors.lastname: Gruppi
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health &Science University, Portland, Oregon 97239, United States.
authors.forename: Nathan
authors.initials: N
authors.lastname: Donley
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Harris
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States.
authors.forename: Carmelo J
authors.initials: CJ
authors.lastname: Rizzo
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health &Science University, Portland, Oregon 97239, United States.|Department of Molecular and Medical Genetics, Oregon Health &Science University, Portland, Oregon 97239, United States.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: McCullough
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health &Science University, Portland, Oregon 97239, United States.|Department of Physiology and Pharmacology, Oregon Health &Science University, Portland, Oregon 97239, United States.
authors.forename: R Stephen
authors.initials: RS
authors.lastname: Lloyd
mesh_terms: D001080:Apurinic Acid / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D055162:Biocatalysis; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D053837:DNA Cleavage; D004249:DNA Damage; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*
chemical_list: D001080:Apurinic Acid; D004247:DNA; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase