Bar-On_2002_Biochemistry_41_3555

Reference

Title : Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine - Bar-On_2002_Biochemistry_41_3555
Author(s) : Bar-On P , Millard CB , Harel M , Dvir H , Enz A , Sussman JL , Silman I
Ref : Biochemistry , 41 :3555 , 2002
Abstract :

Rivastigmine, a carbamate inhibitor of acetylcholinesterase, is already in use for treatment of Alzheimer's disease under the trade name of Exelon. Rivastigmine carbamylates Torpedo californica acetylcholinesterase very slowly (k(i) = 2.0 M(-1) min(-1)), whereas the bimolecular rate constant for inhibition of human acetylcholinesterase is >1600-fold higher (k(i) = 3300 M(-1) min(-1)). For human butyrylcholinesterase and for Drosophila melanogaster acetylcholinesterase, carbamylation is even more rapid (k(i) = 9 x 10(4) and 5 x 10(5) M(-1) min(-1), respectively). Spontaneous reactivation of all four conjugates is very slow, with <10% reactivation being observed for the Torpedo enzyme after 48 h. The crystal structure of the conjugate of rivastigmine with Torpedo acetylcholinesterase was determined to 2.2 A resolution. It revealed that the carbamyl moiety is covalently linked to the active-site serine, with the leaving group, (-)-S-3-[1-(dimethylamino)ethyl]phenol, being retained in the "anionic" site. A significant movement of the active-site histidine (H440) away from its normal hydrogen-bonded partner, E327, was observed, resulting in disruption of the catalytic triad. This movement may provide an explanation for the unusually slow kinetics of reactivation.

PubMedSearch : Bar-On_2002_Biochemistry_41_3555
PubMedID: 11888271
Gene_locus related to this paper: torca-ACHE

Related information

Inhibitor NAP    ENA-713~Rivastigmine
Gene_locus NAP    ENA-713~Rivastigmine    torca-ACHE
Structure NAP    ENA-713~Rivastigmine    torca-ACHE    1GQR    1GQS

Citations formats

Bar-On P, Millard CB, Harel M, Dvir H, Enz A, Sussman JL, Silman I (2002)
Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine
Biochemistry 41 :3555

Bar-On P, Millard CB, Harel M, Dvir H, Enz A, Sussman JL, Silman I (2002)
Biochemistry 41 :3555