Barak_2009_Biochem.J_417_213

Reference

Title : Accommodation of physostigmine and its analogues by acetylcholinesterase is dominated by hydrophobic interactions - Barak_2009_Biochem.J_417_213
Author(s) : Barak D , Ordentlich A , Stein D , Yu QS , Greig NH , Shafferman A
Ref : Biochemical Journal , 417 :213 , 2009
Abstract :

The role of the functional architecture of the HuAChE (human acetylcholinesterase) in reactivity toward the carbamates pyridostigmine, rivastigmine and several analogues of physostigmine, that are currently used or considered for use as drugs for Alzheimer's disease, was analysed using over 20 mutants of residues that constitute the interaction subsites in the active centre. Both steps of the HuAChE carbamylation reaction, formation of the Michaelis complex as well as the nucleophilic process, are sensitive to accommodation of the ligand by the enzyme. For certain carbamate/HuAChE combinations, the mode of inhibition shifted from a covalent to a noncovalent type, according to the balance between dissociation and covalent reaction rates. Whereas the charged moieties of pyridostigmine and rivastigmine contribute significantly to the stability of the corresponding HuAChE complexes, no such effect was observed for physostigmine and its analogues, phenserine and cymserine. Moreover, physostigmine-like ligands carrying oxygen instead of nitrogen at position -1 of the tricyclic moiety (physovenine and tetrahydrofurobenzofuran analogues) displayed comparable structure-function characteristics toward the various HuAChE enzymes. The essential role of the HuAChE hydrophobic pocket, comprising mostly residues Trp(86) and Tyr(337), in accommodating (-)-physostigmine and in conferring approximately 300-fold stereoselectivity toward physostigmines, was elucidated through examination of the reactivity of selected HuAChE mutations toward enantiomeric pairs of different physostigmine analogues. The present study demonstrates that certain charged and uncharged ligands, like analogues of physostigmine and physovenine, seem to be accommodated by the enzyme mostly through hydrophobic interactions.

PubMedSearch : Barak_2009_Biochem.J_417_213
PubMedID: 18729824

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Citations formats

Barak D, Ordentlich A, Stein D, Yu QS, Greig NH, Shafferman A (2009)
Accommodation of physostigmine and its analogues by acetylcholinesterase is dominated by hydrophobic interactions
Biochemical Journal 417 :213

Barak D, Ordentlich A, Stein D, Yu QS, Greig NH, Shafferman A (2009)
Biochemical Journal 417 :213