Alzheimer's disease (AD) is a rising ailment of the elderly, causing loss of cognition and poor quality of life. Efforts to discover the cause are many, however the treatments are few. The fundamental goal of this project is to explore the promiscuity of human choline acetyltransferase (hChAT) for use as a tool in developing a novel high-throughput screen (HTS) searching for new cholinesterase inhibitors (ChEis) for the treatment of AD. We propose using the substrate and cosubstrate promiscuity of hChAT to chemoenzymatically generate acetylcholine analogs and develop a methodology to identify novel ChEis in a HTS fashion. To broaden the panel of chemoenzymatically synthesized acetylcholine analogs hChAT is mutated at several residues to broaden its cosubstrate and substrate promiscuity in addition to amplifying activity via posttranslational phosphorylation. We have found hChAT to accept a variety of choline analogs and a variety of acetyl-CoA analogs. We are currently testing mutants for activity and phosphorylated hChAT for greater activity.

Exploration and expansion of hChAT promiscuity to generate ChEis

239th National Meeting (2010)

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