The lack of newly developed antibiotics, together with the increase in multi-resistance of relevant pathogenic bacteria in the last decades, represents an alarming signal for human health care worldwide. The number of...The lack of newly developed antibiotics, together with the increase in multi-resistance of relevant pathogenic bacteria in the last decades, represents an alarming signal for human health care worldwide. The number of severely infected persons increases not only in developing but also in highly industrialized countries. This relates in first line to the most severe form of a bacterial infection, sepsis and the septic shock syndrome, with high mortality on critical care units. No particular anti-sepsis drug is available, and the therapy with conventional antibiotics more and more fails to provide a survival benefit. Due to the fact that the pharmaceutical industry has withdrawn to a high degree from the development of anti-infectious agents, a huge challenge for health care is approaching in the 21 st century. In this article, these problems are outlined and possible alternatives are presented which may be helpful to solve the problem.展开更多
Dysregulation of the disintegrin-metalloproteinase ADAM10 may contribute to the development of diseases including tumorigenesis and Alzheimer's disease.The mechanisms underlying ADAM10 sheddase activation are inco...Dysregulation of the disintegrin-metalloproteinase ADAM10 may contribute to the development of diseases including tumorigenesis and Alzheimer's disease.The mechanisms underlying ADAM10 sheddase activation are incompletely understood.Here,we show that transient exposure of the negatively charged phospholipid phosphatidylserine(PS)is necessarily required.The soluble PS headgroup was found to act as competitive inhibitor of substrate cleavage.Overexpression of the Ca2+-dependent phospholipid scramblase Anoctamin-6(AN06)led to increased PS externalization and substrate release.Transfection with a constitutively active form of AN06 resulted in maximum sheddase activity in the absence of any stimulus.Calcium-dependent ADAM10 activation could not be induced in lymphocytes of patients with Scott syndrome harbouring a missense mutation in AN06.A putative PS-binding motif was identified in the conserved stalk region.Replacement of this motif resulted in strong reduction of sheddase activity.In conjunction with the recently described 3D structure of the ADAM10 extracellular domain,a model is advanced to explain how surface-exposed PS triggers ADAM 10 sheddase function.展开更多
基金Supported by German ministry BMBF for financial help,Nos.01GUO824 and 01GUO826
文摘The lack of newly developed antibiotics, together with the increase in multi-resistance of relevant pathogenic bacteria in the last decades, represents an alarming signal for human health care worldwide. The number of severely infected persons increases not only in developing but also in highly industrialized countries. This relates in first line to the most severe form of a bacterial infection, sepsis and the septic shock syndrome, with high mortality on critical care units. No particular anti-sepsis drug is available, and the therapy with conventional antibiotics more and more fails to provide a survival benefit. Due to the fact that the pharmaceutical industry has withdrawn to a high degree from the development of anti-infectious agents, a huge challenge for health care is approaching in the 21 st century. In this article, these problems are outlined and possible alternatives are presented which may be helpful to solve the problem.
文摘Dysregulation of the disintegrin-metalloproteinase ADAM10 may contribute to the development of diseases including tumorigenesis and Alzheimer's disease.The mechanisms underlying ADAM10 sheddase activation are incompletely understood.Here,we show that transient exposure of the negatively charged phospholipid phosphatidylserine(PS)is necessarily required.The soluble PS headgroup was found to act as competitive inhibitor of substrate cleavage.Overexpression of the Ca2+-dependent phospholipid scramblase Anoctamin-6(AN06)led to increased PS externalization and substrate release.Transfection with a constitutively active form of AN06 resulted in maximum sheddase activity in the absence of any stimulus.Calcium-dependent ADAM10 activation could not be induced in lymphocytes of patients with Scott syndrome harbouring a missense mutation in AN06.A putative PS-binding motif was identified in the conserved stalk region.Replacement of this motif resulted in strong reduction of sheddase activity.In conjunction with the recently described 3D structure of the ADAM10 extracellular domain,a model is advanced to explain how surface-exposed PS triggers ADAM 10 sheddase function.
