From Split to Sibenik: the tortuous pathway in the cholinesterase field.
The interim between the first and tenth International Cholinesterase Meetings has seen remarkable advances associated with the applications of structural biology and recombinant DNA methodology to our field. The cloning of the cholinesterase genes led to the identification of a new super family of proteins, termed the alpha,beta-hydrolase fold; members of this family possess a four helix bundle capable of linking structural subunits to the functioning globular protein. Sequence comparisons and three-dimensional structural studies revealed unexpected cousins possessing this fold that, in turn, revealed three distinct functions for the alpha,beta-hydrolase proteins. These encompass: (1) a capacity for hydrolytic cleavage of a great variety of substrates, (2) a heterophilic adhesion function that results in trans-synaptic associations in linked neurons, (3) a chaperone function leading to stabilization of nascent protein and its trafficking to an extracellular or secretory storage location. The analysis and modification of structure may go beyond understanding mechanism, since it may be possible to convert the cholinesterases to efficient detoxifying agents of organophosphatases assisted by added oximes. Also, the study of the relationship between the alpha,beta-hydrolase fold proteins and their biosynthesis may yield means by which aberrant trafficking may be corrected, enhancing expression of mutant proteins. Those engaged in cholinesterase research should take great pride in our accomplishments punctuated by the series of ten meetings. The momentum established and initial studies with related proteins all hold great promise for the future.
Taylor
Palmer
P
Department of Pharmacology 0636, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0650, USA. pwtaylor@ucsd.edu
D000110:Acetylcholinesterase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002802:Cholinesterases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans
D000931:Antidotes; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase; D002802:Cholinesterases