Ulrich F Heiser

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Because of their abundance, resistance to proteolysis, rapid aggregation and neurotoxicity, N-terminally truncated and, in particular, pyroglutamate (pE)-modified Abeta peptides have been suggested as being important in the initiation of pathological cascades resulting in the development of Alzheimer's disease. We found that the N-terminal pE-formation is(More)
The membrane-bound glycoprotein dipeptidyl peptidase IV (DP IV, CD26) is a unique multifunctional protein, acting as receptor, binding and proteolytic molecule. We have determined the sequence and 1.8 A crystal structure of native DP IV prepared from porcine kidney. The crystal structure reveals a 2-2-2 symmetric tetrameric assembly which depends on the(More)
Dipeptidyl peptidase IV (DP IV) inhibitors are currently being developed to prolong the biological activity of insulinotropic peptides as a novel approach in the treatment of diabetes. We hypothesised that DP IV inhibition could attenuate the satiety actions of peptide YY (PYY) by altering the conversion of PYY(1–36) to PYY(3–36). The effects of PYY(More)
Glucagon is a 29-amino acid polypeptide released from pancreatic islet alpha-cells that acts to maintain euglycemia by stimulating hepatic glycogenolysis and gluconeogenesis. Despite its importance, there remains controversy about the mechanisms responsible for glucagon clearance in the body. In the current study, enzymatic metabolism of glucagon was(More)
Prolyl endopeptidase (PEP) is a proline-specific oligopeptidase with a reported effect on learning and memory in different rat model systems. Using the astroglioma cell line U343, PEP expression was reduced by an antisense technique. Measuring different second-messenger concentrations revealed an inverse correlation between inositol 1,4,5-triphosphate(More)
Formation of N-terminal pyroglutamate (pGlu or pE) from glutaminyl or glutamyl precursors is catalyzed by glutaminyl cyclases (QC). As the formation of pGlu-amyloid has been linked with Alzheimer's disease, inhibitors of QCs are currently the subject of intense development. Here, we report three crystal structures of N-glycosylated mammalian QC from humans(More)
The first effective inhibitors for human glutaminyl cyclase (QC) are described. The structures are developed by applying a ligand-based optimization approach starting from imidazole. Screening of derivatives of that heterocycle led to compounds of the imidazol-1-yl-alkyl thiourea type as a lead scaffold. A library of thiourea derivatives was synthesized,(More)
The enzymatic conversion of one chromogenic substrate, l-glutamine-p-nitroanilide, and two fluorogenic substrates, l-glutaminyl-2-naphthylamide and l-glutaminyl-4-methylcoumarinylamide, into their respective pyroglutamic acid derivatives by glutaminyl cyclase (QC) was estimated by introducing a new coupled assay using pyroglutamyl aminopeptidase as the(More)
Rheumatoid arthritis is characterised by synovial inflammation and proliferation of fibroblast-like synoviocytes. The induction of apoptosis has long been proposed as a target for proliferative autoimmune diseases, and has further been shown to act as a successful treatment of experimental models of arthritis, such as collagen-induced arthritis. Here we(More)
Mammalian cell lines were examined concerning their Glutaminyl Cyclase (QC) activity using a HPLC method. The enzyme activity was suppressed by a QC specific inhibitor in all homogenates. Aim of the study was to prove whether inhibition of QC modifies the posttranslational maturation of N-glutamine and N-glutamate peptide substrates. Therefore, the impact(More)