Natural products constitute important lead structures in drug discovery. In bacteria, they are often synthesized by large, modular multienzyme complexes. Detailed analysis of the biosynthetic machinery should enable its directed engineering and production of desirable analogs. The myxobacterium Sorangium cellulosum So ce90 produces the cytotoxic spiroketal polyketide spirangien, for which we describe the identification and functional analysis of the biosynthetic pathway. The gene cluster spans 88 kb and encodes 7 type I polyketide synthases and additional enzymes such as a stand-alone thioesterase and 2 methyltransferases. Inactivation of two cytochrome P(450) monooxygenase genes resulted in the production of acyclic spirangien derivatives, providing direct evidence for the involvement of these enzymes in spiroketal formation. The presence of large DNA repeats is consistent with multiple rounds of gene duplication during the evolution of the biosynthetic gene locus.
While many evidences indicate that deficits of central noradrenergic neurotransmission are involved in the age-related decline of cognitive functions in animals and man, very little is known about the specific role of central alpha1-adrenergic receptors. Therefore, this problem was specifically addressed in the present communication using the alpha1-adrenoceptor antagonist prazosin as pharmacological tool. While the acute administration of prazosin did not affect passive avoidance learning of young or aged mice, an improvement of learning capabilities was seen after subchronic treatment, but for the aged animals only. An U-shaped dose response curve was seen. 0.3 mg/kg prazosin was most effective. Very interestingly, only for this dose a significant up-regulation of the density of alpha1-adrenoceptors in the mouse brain was found in the aged animals only. The data suggest a possible causal relationship between effects of prazosin on passive avoidance learning and central alpha1-receptor density.
The effects of local perfusion with the competitive NMDA receptor antagonist 2-amino-5-phosphonovalerate (AP-5) and the glutamate receptor agonist N-methyl-D-aspartate (NMDA) on release of extracellular acetylcholine (ACh) and choline (Ch) in the dorsolateral striatum were studied using in vivo microdialysis in freely moving rats. AP-5 caused a dose-dependent decrease in ACh release that was counteracted by the addition of NMDA. Perfusion with AP-5 also decreased Ch levels. Local perfusion with NMDA induced an elevation of ACh release in low (10(-5) M), but not high (10(-2) M and 10(-3) M) concentrations, that were associated with massive cellular death. These inhibitory effects of AP-5 and the stimulatory effect of NMDA in non-neurotoxic dosages on ACh release provide further evidence for a tonic stimulation of striatal cholinergic interneurons by glutamatergic neurons via NMDA receptors.
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