New insights into copper monooxygenases and peptide amidation: structure, mechanism and function

Many bioactive peptides must be amidated at their carboxy terminus to exhibit full activity. Surprisingly, the amides are not generated by a transamidation reaction. Instead, the hormones are synthesized from glycine-extended intermediates that are transformed into active amidated hormones by oxidative cleavage of the glycine N-C alpha bond. In higher organisms, this reaction is catalyzed by a single bifunctional enzyme, peptidylglycine alpha-amidating monooxygenase (PAM). The PAM gene encodes one polypeptide with two enzymes that catalyze the two sequential reactions required for amidation. Peptidylglycine alpha-hydroxylating monooxygenase (PHM; EC 1.14.17.3) catalyzes the stereospecific hydroxylation of the glycine alpha-carbon of all the peptidylglycine substrates. The second enzyme, peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL; EC 4.3.2.5), generates alpha-amidated peptide product and glyoxylate. PHM contains two redox-active copper atoms that, after reduction by ascorbate, catalyze the reduction of molecular oxygen for the hydroxylation of glycine-extended substrates. The structure of the catalytic core of rat PHM at atomic resolution provides a framework for understanding the broad substrate specificity of PHM, identifying residues critical for PHM activity, and proposing mechanisms for the chemical and electron-transfer steps in catalysis. Since PHM is homologous in sequence and mechanism to dopamine beta-monooxygenase (DBM; EC 1.14.17.1), the enzyme that converts dopamine to norepinephrine during catecholamine biosynthesis, these structural and mechanistic insights are extended to DBM.     

Regulation of the type III InsP3 receptor and its role in beta cell function

The type III inositol 1,4,5-trisphosphate receptor (InsP3R) is an important intracellular calcium (Ca2+) release channel in the pancreatic beta cell. Pancreatic beta cells secrete insulin following a characteristic change in membrane potential that leads to an increase in cytoplasmic Ca2+. Both extracellular Ca2+ and Ca2+ mobilized from InsP3-sensitive stores contribute to this increase. RIN-m5F cells, an insulin-secreting beta cell line, preferentially express the type III InsP3R. These cells have been useful in determining the regulatory properties of the type III InsP3R and the role of this isoform in an intact cell. The type III InsP3R is ideal for signal initiation because high cytoplasmic Ca2+ does not inhibit its activity. Altered insulin secretion, the result of changes in Ca2+ handling by the beta cell, has significant clinical consequences.     

Effect of the mast cell disruptor B.W. 48/80 on dietary atherosclerosis in the male rabbit

Zusammenfassung Mit Cholesterin ernährte Kaninchen, denen gleichzeitig Compound 48/80 injiziert wurde, wiesen gegenüber nur mit Cholesterinzusatz gefütterten Tieren geringere Atheromatose des Aortenbogens auf. Compound 48/80 rief auch eine Verminderung des Serumcholesteringehaltes hervor. Unter dem Einfluss von Compound 48/80 schien ein beschleunigter Abbau der atheromatösen Plaques einzusetzen bevor noch eine Verminderung des Serumcholesterins auftrat. Es wird vermutet, dass der Schutz von Compound 48/80 gegen die durch Diät erzeugte Atheromatose des Kaninchens auf einer Veränderung des arteriellen Glykosaminglykans beruht.     

Mite parasitism of moths: Examples of paleosymbiosis in Dominican amber

Summary Two adult moths (families Gracillariidae and Tineidae) in Dominican amber each contained a pair of larval parasitic mites attached to their bodies. The larval mites were identified as belonging to the family Erythraeidae and represent the first fossil evidence of moths parasitized by mites. Phylogenic and evolutionary implications of this find are discussed in light of similar extant associations.     

Visual spatial memory in desert ants,Cataglyphis bicolor (Hymenoptera: Formicidae)

Summary For navigation, desert ants apply piloting and dead-reckoning strategies based on terrestrial and celestial visual cues, respectively. Visual spatial memories, rather than general concepts derived from landmark constellations, are most probably used to define points on earth by nearby landmarks. The visual field of a specialized dorsal part of the ant's retina is mapped on to the celestial sphere to consider the possibility that similar mechanisms are used to define directions on earth by exploiting skylight patterns present at infinity.Supported by the Hescheler Foundation (Zurich) and the Swiss National Science Foundation grants Nos 3.529-0.75 and 3.313-0.78.     

ACTH-induced hyperalgesia in rats.

The injection of ACTH 1--24 into the cerebral ventricles in rats markedly reduces the reaction time in the hot-plate test and the nociception threshold in the tail-stimulation test. Morphine antagonizes and naloxone potentiates this hyperalgesic effect of ACTH. It is proposed that ACTH peptides play a physiological role in nociception.