Structural dynamics and catalytic modulations of Aβ regulating enzymes as future outlook for Alzheimer's

Abstract

Aβ cascade hypothesis being considered most evident event in AD pathology and even today it holds good. Dysregulation of catalytic events of Aβ regulating enzymes can possibly cause faulty Aβ trafficking; inequity of Aβ formation and clearance resulting in misfolded protein accumulation, neurodegeneration and cognitive impairment. Many novel approaches have been made on this pathway to discover new molecules, unfortunately couldn't reach the terminal phases of clinical trials. Over decades, studies have been more focused on enzyme chemistry and explored the relationship between structural features and catalytic function of Aβ regulating enzymes. However, the modulations of catalytic mechanisms of those enzymes have not been imposed so far to reduce the Aβ load. Hence, in this review, we have critically detailed the knowledge of basic structural dynamics and possible catalytic modulations of enzymes responsible for Aβ formation and clearance that will impart new perspectives in drug discovery process.

Keywords: Allosteric modulation; Aβ oligomers; Catalytic pockets; Drug discovery; Proteolytic enzymes.