The role of TRP84 in catalytic power and the specificity of AChE.
The structure-function relationship between the alkaloids physostigmine, physovenine and the three structurally related compounds were investigated by employing kinetic studies and molecular modeling. Crystallographic data from the X-ray conformation of the Torpedo californica acetylcholinesterase complex together with the transition state analog inhibitor m-(N,N,N,-Trimethylammonio) trifluoroacetophenone (TMTFA) was used as template onto which inhibitors were superimposed. Among the structural elements of the active site, TRP84 residue shows a versatile role. In fact, its aromatic electrons not only can be employed in pi-cation interactions, as is the case for ACh, but they can also provide a polarizable surface for van der Waals and London interactions.
Pomponi
M
M
Istituto di Chimica e Chimica Clinica, Facoltà di Medicina, UCSC, Rome, Italy. m.pomponi@uniserv.ccr.rm.cnr.it
Sacchi
S
S
Colella
A
A
Patamia
M
M
Marta
M
M
D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002384:Catalysis; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D008958:Models, Molecular; D010830:Physostigmine / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013816:Thermodynamics; D014101:Torpedo; D014364:Tryptophan / Q000737:chemistry*
D002800:Cholinesterase Inhibitors; D007202:Indicators and Reagents; D014364:Tryptophan; D010830:Physostigmine; D000110:Acetylcholinesterase