Toward bifunctional antibody catalysis.
Antibodies that catalyze the deprotonation of unactivated benzisoxazoles to give the corresponding salicylonitriles were prepared using as antigen a 2-aminobenzimidazolium derivative coupled to a carrier protein via its benzene ring. The hapten was designed to induce an antibody binding site with both a base and an acid, in position to initiate proton transfer and stabilize developing negative charge at the phenoxide leaving group, respectively. Consistent with this design, the catalysts exhibit bell-shaped pH-rate profiles, while chemical modification identified several functional groups that could participate in bifunctional catalysis. One of the antibodies, 13G5, is particularly notable in catalyzing the elimination of 6-glutaramidebenzisoxazole with a > 10(5)-fold rate acceleration over background and an effective molarity of > 10(4) M for its catalytic base. These properties compare favorably to the efficiencies achieved by the best previously characterized antibodies with substantially more reactive substrates.
Kikuchi
Kazuya
K
Department of Chemistry, The Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Hannak
Renate B
RB
Guo
Mao-Jun
MJ
Kirby
Anthony J
AJ
Hilvert
Donald
D
D017151:Antibodies, Catalytic / Q000096:biosynthesis / Q000737:chemistry*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D002384:Catalysis; D006241:Haptens / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013954:Thyroglobulin / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification
D017151:Antibodies, Catalytic; D001562:Benzimidazoles; D006241:Haptens; D013954:Thyroglobulin; C027391:2-aminobenzimidazole