Fortschritte Der Chemie Organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products

ISBN-13: 9783211831656 / Angielski / Twarda / 1998 / 211 str.

L. Zeichmeister; W. Herz; L. Zechmeister

Opis

In order to make further progress in elucidating the mechanism of NOS catalysis it will be essential to throw light on the interaction between the enzyme and its substrate. An understanding of the catalytic site will also assist the development of therapeutically important NOS inhibitors. In particular. it will be useful to uncover any differences that exist between the substrate binding sites of the three NOS isozymes which might be exploited for the development of isoform selective NOS inhibitors. A comparison of NOS to other Arg-binding proteins has shown no significant sequence homology (159). Moreover, the lack of a 3D structure and absence of significant sequence homology between the NOS oxygenase domain and known cytochromes P450 has made it difficult to identify residues and construct a model of the distal heme pocket responsible for substrate binding. However, a number of groups are currently working towards crystallisation of the separate NOS reductase and oxygenase domains of the three isoforms for X-ray diffraction studies; the first X-ray structure is likely to be forthcoming within a matter of months. * The results of these studies are expected to resolve many of the uncertainties surrounding the structure of the NOS catalytic site. Preliminary X-ray diffraction analysis of CPR from rat liver has already been reported by MASTERS et al. (524) and the future emergence of a detailed structure for this protein should throw light on the structure and function of the NOS reductase domain.

Spis treści

Nitric Oxide: Physiological Roles, Biosynthesis and Medical Uses.- List of Abbreviations and Acronyms.- 1. Introduction.- 2. Discovery in the Vasculature.- 3. Platelet Aggregation.- 4. NO and the Immune System.- 5. NO and the Nervous System.- 6. S-Nitrosothiols.- 6.1. NO-Release.- 6.2. Endogenous S-Nitrosothiols.- 6.3. S-Nitrosothiols as NO-Donor Drugs.- 7. NO Activity in the Mammalian Eye.- 8. The NO Biosynthetic Pathway.- 8.1. Introduction.- 8.2. Relation of Nitric Oxide Synthase to Cytochrome P 450.- 8.3. NO Synthase Isoforms.- 9. Mechanism of the Nitric Oxide Synthase-Catalysed Reaction.- 9.1. Mechanism of Cytochrome P450-Mediated Oxidations.- 9.1.1. P450-Mediated Hydroxylation.- 9.1.2. P450-Mediated N-Oxidation and N-Dealkylation.- 9.1.3. P450-Mediated Epoxidation.- 9.1.4. Aromatase Chemistry.- 9.2. Mechanism of NOS Monooxygenation I.- 9.3. Mechanism of NOS Monooxygenation II.- 9.4. Mechanism-Based Inhibitors of NOS.- 9.5. Summary.- 10. Nitric Oxide Synthase Structure.- 10.1. Primary Structure and Domain Organisation of NOS.- 10.1.1. Primary Structure.- 10.1.2. Domain Organisation.- 10.2. Function of the NOS Reductase Domain.- 10.3. The Calmodulin Binding Site.- 10.4. Membrane Association of NOS.- 10.5. Structure and Topology of the NOS Catalytic Site.- 10.5.1. Identification of Heme Thiolate Ligand.- 10.5.2. Characterisation of the NOS Heme Spin State.- 10.5.3. Structure of the NOS Catalytic Site.- 10.5.4. Identification of Residues that contribute to the Catalytic Site.- 10.5.5. Complementation Analysis with NOS Heterodimers.- 10.5.6. Summary.- 10.6 Role of the Biopterin Cofactor in NOS Catalysis.- 10.6.1. NOS and Pteridine-Dependent Hydroxylases: Dissimilarity in the Catalytic Role of H4B.- 10.6.2. An Allosteric Role for H4B in NOS Catalysis.- 10.6.3. A Redox Role for H4B in NOS Catalysis.- 10.6.4. The H4B Binding Site.- 10.7. NOS Dimer Assembly.- 10.8. Autoinactivation/NO Feedback Inhibition of NOS.- 10.9. Distinctive Features of NOS Isoforms.- 11. Clinical Uses of NO and Its Inhibitors.- 11.1. Respiratory Systems.- 11.2. Airway Modulation and Asthma.- 11.3. Toxicology.- 11.4. Adult Respiratory Distress Syndrome.- 11.5. Sepsis.- 11.6. NO, Inflammation, and the Immune System.- 11.7. NOS Inhibition in Sepsis.- 11.8. NO and Cardiovascular Disease.- 11.9. NO and Interventional Cardiology.- 11.10. Pregnancy.- 11.11. Pre-Eclampsia.- 11.12. Nervous System.- 11.13. Bone.- 11.14. Conclusion.- 12. Addendum.- Acknowledgements.- References.- Author Index.