title: Evidence for essential histidines in human pituitary glutaminyl cyclase.
abstract: Glutaminyl cyclase (QC, EC 2.3.2.5) catalyzes the formation of the pyroglutamyl residue present at the amino terminus of numerous secretory peptides and proteins. Treatment with diethyl pyrocarbonate inactivated recombinant human QC with the apparent modification of three essential histidine residues. Comparisons of the protein sequences of QC from a variety of eukaryotic species show four completely conserved histidine residues. Mutation of each of these residues to glutamine resulted in two mutant enzymes that were inactive (H140Q and H330Q), suggesting a role in catalysis, and two that exhibited increased Km values (H307Q and H319Q), suggesting a role in substrate binding. Consistent with these results is the prediction that QC possesses a zinc aminopeptidase domain in which the four histidines identified here are present in the active site. Mammalian glutaminyl cyclases may, therefore, have structural and catalytic similarities to a family of bacterial zinc aminopeptidases.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Southern Mississippi, Hattiesburg, Mississippi 39406-5043, USA. Robert.Bateman@usm.edu
authors.forename: R C
authors.initials: RC
authors.lastname: Bateman
authors.forename: J S
authors.initials: JS
authors.lastname: Temple
authors.forename: S A
authors.initials: SA
authors.lastname: Misquitta
authors.forename: R E
authors.initials: RE
authors.lastname: Booth
mesh_terms: D000595:Amino Acid Sequence; D019881:Aminoacyltransferases / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D000626:Aminopeptidases / Q000145:classification; D017124:Conserved Sequence; D004047:Diethyl Pyrocarbonate; D006639:Histidine; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010902:Pituitary Gland / Q000201:enzymology*; D017386:Sequence Homology, Amino Acid
chemical_list: D006639:Histidine; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D000626:Aminopeptidases; D004047:Diethyl Pyrocarbonate