Mothana S

References (2)

Title : Carbamates with differential mechanism of inhibition toward acetylcholinesterase and butyrylcholinesterase - Darvesh_2008_J.Med.Chem_51_4200
Author(s) : Darvesh S , Darvesh KV , McDonald RS , Mataija D , Walsh R , Mothana S , Lockridge O , Martin E
Ref : Journal of Medicinal Chemistry , 51 :4200 , 2008
Abstract : 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 pi-pi 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 pi-cationic site of the Omega-loop, the E-helix represents a domain that could be exploited for development of specific inhibitors to treat dementias.
ESTHER : Darvesh_2008_J.Med.Chem_51_4200
PubMedSearch : Darvesh_2008_J.Med.Chem_51_4200
PubMedID: 18570368

Title : On the active site for hydrolysis of aryl amides and choline esters by human cholinesterases - Darvesh_2006_Bioorg.Med.Chem_14_4586
Author(s) : Darvesh S , McDonald RS , Darvesh KV , Mataija D , Mothana S , Cook H , Carneiro KM , Richard N , Walsh R , Martin E
Ref : Bioorganic & Medicinal Chemistry , 14 :4586 , 2006
Abstract : Cholinesterases, in addition to their well-known esterase action, also show an aryl acylamidase (AAA) activity whereby they catalyze the hydrolysis of amides of certain aromatic amines. The biological function of this catalysis is not known. Furthermore, it is not known whether the esterase catalytic site is involved in the AAA activity of cholinesterases. It has been speculated that the AAA activity, especially that of butyrylcholinesterase (BuChE), may be important in the development of the nervous system and in pathological processes such as formation of neuritic plaques in Alzheimer's disease (AD). The substrate generally used to study the AAA activity of cholinesterases is N-(2-nitrophenyl)acetamide. However, use of this substrate requires high concentrations of enzyme and substrate, and prolonged periods of incubation at elevated temperature. As a consequence, difficulties in performing kinetic analysis of AAA activity associated with cholinesterases have hampered understanding this activity. Because of its potential biological importance, we sought to develop a more efficient and specific substrate for use in studying the AAA activity associated with BuChE, and for exploring the catalytic site for this hydrolysis. Here, we describe the structure-activity relationships for hydrolysis of anilides by cholinesterases. These studies led to a substrate, N-(2-nitrophenyl)trifluoroacetamide, that was hydrolyzed several orders of magnitude faster than N-(2-nitrophenyl)acetamide by cholinesterases. Also, larger N-(2-nitrophenyl)alkylamides were found to be more rapidly hydrolyzed by BuChE than N-(2-nitrophenyl)acetamide and, in addition, were more specific for hydrolysis by BuChE. Thus, N-(2-nitrophenyl)alkylamides with six to eight carbon atoms in the acyl group represent suitable specific substrates to investigate further the function of the AAA activity of BuChE. Based on the substrate structure-activity relationships and kinetic studies, the hydrolysis of anilides and esters of choline appears to utilize the same catalytic site in BuChE.
ESTHER : Darvesh_2006_Bioorg.Med.Chem_14_4586
PubMedSearch : Darvesh_2006_Bioorg.Med.Chem_14_4586
PubMedID: 16504521