Abstract

Image: Courtesy of Yue-Ming Li HOW PHOTOACTIVATION WORKS: When a benzophenone group is attached to a g-secretase inhibitor and exposed to light, the benzophenone's oxygen turns into a triplet biradical, which bonds covalently with a nearby protein. Many neuroscientists think that the master criminal behind Alzheimer disease is AB-secretase-42, the 42-amino-acid peptide that forms amyloid plaques in the brain. Two accomplices, the enzymes B-secretase-secretase and g-secretase, consecutively cleave AB-secretase from the much larger B-secretase-amyloid precursor protein (APP). What baffles investigators about g-secretase is that its substrate is a stretch of amino acids within APP's seemingly inaccessible transmembrane domain. Many genetic and cellular studies suggest that g-secretase's active site resides in the transmembrane protein presenilin-1 (PS1), which was first reported in 1995.1 Then in 2000, Merck & Co. labs in the United States and Great Britain provided compelling biochemical evidence in a Hot Paper2 favoring that hypothesis. Data derived from the Science Watch/Hot Papers database and the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. Y.-M. Li et al., "Photoactivated g-secretase inhibitors directed to the active site covalently label presenilin