Structure, Mechanism and Inhibition of the human Glutaminyl Cyclase

The mammalian zinc-dependent enzyme glutaminyl cyclase (QC, EC 2.3.2.5) belongs to the family of transferases and plays a crucial role in hormone maturation by cyclizing irreversibly N-terminal glutamines post-translationally to pyroglutamic acid (5-oxo-L-proline, pGlu) via a deamidation reaction. Although, the physiological function of pGlu at the N-terminus seems to be essential for generation of biologically active structures, it was reported that QC is also capable to catalyze the intramolecular cyclization of N-terminal glutamic acid precursors via a dehydration reaction, which is directly connected with pathophysiological processes, especially in amyloidogenic diseases. Moreover, recent studies have shown that QC activity is abundant in brain regions, e.g. hypothalamus, and that the enzyme is probably responsible for the modification of truncated ß-amyloid (Aß) peptide species at their N-terminus in the course of Alzheimer’s disease (AD). Thus, mammalian QC might play a crucial role in the formation of the progressive neurodegenerative disorder, especially in the initial phase, and is therefore a potential drug target candidate in the therapeutic strategy to prevent amyloidogenic plaque formation. The aim of this work is to decipher the reaction mechanism of human QC in detail and based on this work to design a selective and potent inhibitor.