TY - JOUR
T1 - Carbamates with differential mechanism of inhibition toward acetylcholinesterase and butyrylcholinesterase
AU - Darvesh, Sultan
AU - Darvesh, Katherine V.
AU - McDonald, Robert S.
AU - Mataija, Diane
AU - Walsh, Ryan
AU - Mothana, Sam
AU - Lockridge, Oksana
AU - Martin, Earl
PY - 2008/7/24
Y1 - 2008/7/24
N2 - Most carbamates are pseudoirreversible inhibitors of cholinesterases. Phenothiazine carbamates exhibit this inhibition of acetylcholinesterase but produce reversible inhibition of butyrylcholinesterase, suggesting that they do not form a covalent bond with the catalytic serine. This atypical inhibition is attributable to π-π interaction of the phenothiazine moiety with F329 and Y332 in butyrylcholinesterase. These residues are in a helical segment, referred to here as the E-helix because it contains E325 of the catalytic triad. The involvement of the E-helix in phenothiazine carbamate reversible inhibition of butyrylcholinesterase is confirmed using mutants of this enzyme at A328, F329, or Y332 that show typical pseudoirreversible inhibition. Thus, in addition to various domains of the butyrylcholinesterase active site gorge, such as the peripheral anionic site and the π-cationic site of the Ω-loop, the E-helix represents a domain that could be exploited for development of specific inhibitors to treat dementias.
AB - Most carbamates are pseudoirreversible inhibitors of cholinesterases. Phenothiazine carbamates exhibit this inhibition of acetylcholinesterase but produce reversible inhibition of butyrylcholinesterase, suggesting that they do not form a covalent bond with the catalytic serine. This atypical inhibition is attributable to π-π interaction of the phenothiazine moiety with F329 and Y332 in butyrylcholinesterase. These residues are in a helical segment, referred to here as the E-helix because it contains E325 of the catalytic triad. The involvement of the E-helix in phenothiazine carbamate reversible inhibition of butyrylcholinesterase is confirmed using mutants of this enzyme at A328, F329, or Y332 that show typical pseudoirreversible inhibition. Thus, in addition to various domains of the butyrylcholinesterase active site gorge, such as the peripheral anionic site and the π-cationic site of the Ω-loop, the E-helix represents a domain that could be exploited for development of specific inhibitors to treat dementias.
UR - http://www.scopus.com/inward/record.url?scp=47749102491&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=47749102491&partnerID=8YFLogxK
U2 - 10.1021/jm8002075
DO - 10.1021/jm8002075
M3 - Article
C2 - 18570368
AN - SCOPUS:47749102491
VL - 51
SP - 4200
EP - 4212
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 14
ER -