title: Glutaminyl cyclase knock-out mice exhibit slight hypothyroidism but no hypogonadism: implications for enzyme function and drug development.
abstract: Glutaminyl cyclases (QCs) catalyze the formation of pyroglutamate (pGlu) residues at the N terminus of peptides and proteins. Hypothalamic pGlu hormones, such as thyrotropin-releasing hormone and gonadotropin-releasing hormone are essential for regulation of metabolism and fertility in the hypothalamic pituitary thyroid and gonadal axes, respectively. Here, we analyzed the consequences of constitutive genetic QC ablation on endocrine functions and on the behavior of adult mice. Adult homozygous QC knock-out mice are fertile and behave indistinguishably from wild type mice in tests of motor function, cognition, general activity, and ingestion behavior. The QC knock-out results in a dramatic drop of enzyme activity in the brain, especially in hypothalamus and in plasma. Other peripheral organs like liver and spleen still contain QC activity, which is most likely caused by its homolog isoQC. The serum gonadotropin-releasing hormone, TSH, and testosterone concentrations were not changed by QC depletion. The serum thyroxine was decreased by 24% in homozygous QC knock-out animals, suggesting a mild hypothyroidism. QC knock-out mice were indistinguishable from wild type with regard to blood glucose and glucose tolerance, thus differing from reports of thyrotropin-releasing hormone knock-out mice significantly. The results suggest a significant formation of the hypothalamic pGlu hormones by alternative mechanisms, like spontaneous cyclization or conversion by isoQC. The different effects of QC depletion on the hypothalamic pituitary thyroid and gonadal axes might indicate slightly different modes of substrate conversion of both enzymes. The absence of significant abnormalities in QC knock-out mice suggests the presence of a therapeutic window for suppression of QC activity in current drug development.
authors.affiliation: Probiodrug AG, Weinbergweg 22, 06120 Halle/Saale, Germany. stephan.schilling@probiodrug.de
authors.forename: Stephan
authors.initials: S
authors.lastname: Schilling
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kohlmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Bäuscher
authors.forename: Reinhard
authors.initials: R
authors.lastname: Sedlmeier
authors.forename: Birgit
authors.initials: B
authors.lastname: Koch
authors.forename: Rico
authors.initials: R
authors.lastname: Eichentopf
authors.forename: Andreas
authors.initials: A
authors.lastname: Becker
authors.forename: Holger
authors.initials: H
authors.lastname: Cynis
authors.forename: Torsten
authors.initials: T
authors.lastname: Hoffmann
authors.forename: Sabine
authors.initials: S
authors.lastname: Berg
authors.forename: Ernst-Joachim
authors.initials: EJ
authors.lastname: Freyse
authors.forename: Stephan
authors.initials: S
authors.lastname: von Hörsten
authors.forename: Steffen
authors.initials: S
authors.lastname: Rossner
authors.forename: Sigrid
authors.initials: S
authors.lastname: Graubner
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
mesh_terms: D019881:Aminoacyltransferases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015195:Drug Design; D053595:Embryonic Stem Cells / Q000166:cytology; D005260:Female; D007006:Hypogonadism / Q000235:genetics*; D007037:Hypothyroidism / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry; D013739:Testosterone / Q000378:metabolism; D013972:Thyrotropin / Q000378:metabolism
chemical_list: D013739:Testosterone; D013972:Thyrotropin; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D011761:Pyrrolidonecarboxylic Acid