PT  - JOURNAL ARTICLE
AU  - Philip L. Lorenzi
AU  - Christopher P. Landowski
AU  - Andrea Brancale
AU  - Xueqin Song
AU  - Leroy B. Townsend
AU  - John C. Drach
AU  - Gordon L. Amidon
TI  - <em>N</em>-METHYLPURINE DNA GLYCOSYLASE AND 8-OXOGUANINE DNA GLYCOSYLASE METABOLIZE THE ANTIVIRAL NUCLEOSIDE 2-BROMO-5,6-DICHLORO-1-(β-D-RIBOFURANOSYL)BENZIMIDAZOLE
AID  - 10.1124/dmd.105.009209
DP  - 2006 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 1070--1077
VI  - 34
IP  - 6
4099  - http://dmd.aspetjournals.org/content/34/6/1070.short
4100  - http://dmd.aspetjournals.org/content/34/6/1070.full
SO  - Drug Metab Dispos2006 Jun 01; 34
AB  - The rapid in vivo degradation of the potent human cytomegalovirus inhibitor 2-bromo-5,6-dichloro-1-(β-d-ribofuranosyl)benzimidazole (BDCRB) compared with a structural l-analog, maribavir (5,6-dichloro-2-(isopropylamino)-1-β-l-ribofuranosyl-1H-benzimidazole), has been attributed to selective glycosidic bond cleavage. An enzyme responsible for this selective BDCRB degradation, however, has not been identified. Here, we report the identification of two enzymes, 8-oxoguanine DNA glycosylase (OGG1) and N-methylpurine DNA glycosylase (MPG), that catalyze N-glycosidic bond cleavage of BDCRB and its 2-chloro homolog, 2,5,6-trichloro-1-(β-d-ribofuranosyl)benzimidazole, but not maribavir. To our knowledge, this is the first demonstration that free nucleosides are substrates of OGG1 and MPG. To understand how these enzymes might process BDCRB, docking and molecular dynamics simulations were performed with the native human OGG1 crystal coordinates. These studies showed that OGG1 was not able to bind a negative control, guanosine, yet BDCRB and maribavir were stabilized through interactions with various binding site residues, including Phe319, His270, Ser320, and Asn149. Only BDCRB, however, achieved orientations whereby its anomeric carbon, C1′, could undergo nucleophilic attack by the putative catalytic residue, Lys249. Thus, in silico observations were in perfect agreement with experimental observations. These findings implicate DNA glycosylases in drug metabolism. The American Society for Pharmacology and Experimental Therapeutics