Glutaminyl cyclases, the potential targets of cancer and neurodegenerative diseases

Abstract

Glutaminyl cyclases (QC) catalyze the cyclization of proteins and turn N-terminal glutamine or glutamic acid into N-terminal pyroglutamate, resulting in protection of proteins from aminopeptidases and an increase of their stabilities. The aberrant N-terminal pyroglutamate has been found in various diseases, including Alzheimer's disease (AD), Huntington's disease (HD) and cancer. Two kinds of human QC, the secretory sQC and the Golgi resident gQC, are identified to date. Several substrates of sQC involving beta amyloid (Aβ), Huntington (HTT) protein and certain inflammatory mediators such as CCL2 and CX3CL1 have been observed to associate with neurodegenerative diseases and cancers. The Golgi resident gQC can modify N-terminus of CD47 that directly influences the interaction of CD47 and SIRPα resulting in the modulations of the immunological surveillance related mechanisms in cancer. Additionally, inflammatory chemokines CCL2 and CX3CL1 can also be modified by gQC. Several QC inhibitors with differential scaffold structures have been developed and investigated. Among these QC inhibitors, PQ912, a benzimidazole-based inhibitor, has been studied in a phase II clinical trial to treat AD. In this review, we will summarize the current knowledge about QCs' tissue expression patterns, their potential cellular substrates in the context of cancers, AD and HD. After introducing QCs' molecular structures and catalysis mechanisms, the structures and efficacies of the currently reported QCs' inhibitors will also be summarized.

Keywords: Alzheimer's disease; Cancer; Glutaminyl cyclase; Glutaminyl cyclase inhibitors; Pyroglutamate.