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Reactant

Product. Reactant. Energy Landscape. Eco RV. Phosphodiester hydrolysis. H 2 O. “Reactant State” Crystal Structure. Ala 92 (Mutated from Lys). Cleavage Site. 3.7Å. Water Oxygen. Molecular Dynamics of Wild Type. PETRA IMHOF. Lys 92. Water Molecule.

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Reactant

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  1. Product Reactant Energy Landscape

  2. EcoRV

  3. Phosphodiester hydrolysis H2O

  4. “Reactant State” Crystal Structure Ala 92 (Mutated from Lys) Cleavage Site 3.7Å Water Oxygen

  5. Molecular Dynamics of Wild Type PETRA IMHOF Lys 92 Water Molecule

  6. Molecular Dynamics of Wild Type PETRA IMHOF MD I

  7. MD II

  8. Principal Component Principal Components I

  9. Molecular Dynamics of Wild-Type Deprotonated Lys 92 Water Molecule

  10. Muscle Contraction Thin filament Thick filament

  11. SONJA SCHWARZL ATP Hydrolysis by Myosin

  12. SerineProtease Melanie Böttcher

  13. Index • Definition • Digestive enzymes • Blood clotting • Complement system

  14. Serine Protease • Cutting of certain peptide bonds in other proteins • Activity depends on a set of amino acid residues in the active site of the enzyme • Based on nucleophilic attack of the targeted peptidic bond by a serine

  15. Serine • Amino acid • alcohol as residue

  16. Digestive enzymes Chymotrypsin • Chymotrypsin, Trypsin, Elastase • closely-similar structures • different substrate specificities • Pancreatic proteases  proenzymes trypsinogen and chymotrypsinogen  synthesized in the pancreas and secreted into the lumen of the small intestine Elastase Trypsin

  17. Mechanism

  18. Active site

  19. Trypsinogen-Trypsin • loss of six amino acids from one end • overall structures remain similar • Ca++ for thermal stability activated enzyme does have more of its structure organized into sheets

  20. Trypsin • Trypsin cleaves peptide bonds on the C-terminal side of arginines and lysines  Alcaline amino acids • Activation by enteropeptidase or through protoelyse • Optimum pH 7 to 8

  21. Chymotrypsinogen-Chymotrypsin • Chain is clipped in four places  release of 2 dipeptides  creation of two breaks in the backbone • 1-13 segment retained as part of the active enzyme, linked on by a disulfide bond Activation by trypsin

  22. Chymotrypsin • Active site: His57-Ser195-Asp102 • Chymotrypsin cuts on the C-terminal side of tyrosine, phenylalanine, and tryptophan residues • hydrolysis of bonds of leucyl, methionyl, asparaginyl and glutamyl residues.

  23. Elastase • cuts peptide bonds next to small, uncharged side chains such as those of alanine, serine, valine and threonin • cuts collagen

  24. Blood Clotting System • Cascade of several mechanism • Involved Serine Proteases • Thrombin • Plasmin • Factor 10 a • Factor 11 b

  25. Blood Clotting Pathway

  26. Human Thrombin with the Amino acids 55-65 of Hirudin Thrombin • Inactivated Prothrombin cleaves into activated Thrombin • Thrombins cuts Paraglobuline (= fibrinoplastic substance) and forms the soluble state of it • Precipitation by plasmasalt in unsoluble state

  27. Serpins • Serine Protease Inhibitors • inhibit the action of their respective serine protease  serine protease binds the serpin instead of its normal substrate  protease makes a cut in the serpin leading to • the formation of a covalent bond linking the two molecules • a massive allosteric change in the tertiary structure of the serpin which moves the attached protease to a site where it can be destroyed

  28. Occurrence/ Function • stop proteolytic activity • blood plasma • clotting • complement systems where a tiny initial activating event leads to a rapidly amplifying cascade of activity

  29. Serpin Deficiencies • inherited diseases • mutation in the encoding gene for serpin • examples

  30. Alpha-1-Antitrypsin • Serpin for Elastase • secreted by neutrophils (lung infection) • emphysema • liver damage • tests are running

  31. The Others • Other Serine Proteases • Subtilisin • Acetylcholinesterase • Serpinlike Molecules • Angiotensinogen • Chicken Ovalbumin

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