Thrombus

15. Kevin Ahern's Biochemistry - Blood Clotting

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• published: 05 Nov 2013
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1. Contact me at kgahern@davincipress.com / Friend me on Facebook (kevin.g.ahern) 2. Download my free biochemistry book at http://biochem.science.oregonstate.edu/biochemistry-free-and-easy 3. Take my free iTunes U course at https://itunes.apple.com/us/course/biochemistry/id556410409 4. Check out my free book for pre-meds at http://biochem.science.oregonstate.edu/biochemistry-free-and-easy 5. Lecturio videos for medical students - https://www.lecturio.com/medical-courses/biochemistry.course 6. Course video channel at http://www.youtube.com/user/oharow/videos?view=1 7. Check out all of my free workshops at http://oregonstate.edu/dept/biochem/ahern/123.html 8. Check out my Metabolic Melodies at http://www.davincipress.com/ 9. My courses can be taken for credit (wherever you live) via OSU's ecampus. For details, see http://ecampus.oregonstate.edu/soc/ecatalog/ecourselist.htm?termcode=all&subject;=BB 10. Course materials at http://oregonstate.edu/instruct/bb450 Highlights Enzyme Regulation 1. Zymogens are enzymes that are synthesized in an inactive form whose activation requires covalent modification, usually proteolytic cleavage. Examples include digestive enzymes, such as trypsin, chymotrypsin, elastase, and carboxypeptidase whose enzymatic activity might be harmful to the tissue where they are being made. 2. Trypsin is the primary activator of an entire class of proteolytic enzymes. Improper activation of trypsin in or close to the pancreas can lead to pancreatitis, which arises when the proteases attack proteins in the pancreas. 3. Activation of chymotrypsinogen to chymotrypsin, for example, requires trypsin. Trypsin makes an initial cleavage beween amino acids 15 and 16. A disulfide bond keeps the two pieces from coming completely apart, however. This creates an intermediately active form of chymotrypsin called pi-chymotrypsin. This form cleaves itself to remove two dipeptides and this results in full chymotrypsin activity. The three polypeptide pieces are held together by disulfide bonds. Note that three very minor changes in the chymotrypsinogen zymogen have converted a completely inactive enzyme to a fully active one. 4. Alpha one anti-trypsin is a protease inhibitor that stops elastase in the lungs from getting too active. If elastase is too active, emphysema will result. Smokers damage an important methionine in alpha one anti-trypsin, which prevents it from binding to elastase, resulting in elastase getting too active and causing emphysema. 5. Two pathways activate the blood clotting process, the intrinsic pathway and the extrinsic pathway. Ultimately these cascades lead to the conversion of prothrombin (zymogen) to thrombin (active enzyme). Thrombin, in turn, converts fibrinogen (zymogen) to fibrin (mesh former as a result of polymerization). 6. Clipping of the A and B portions of the alpha and beta subunits of fibrinogen (by thrombin) convert it to fibrin and the remaining ends of those chains can insert into structures in the gamma and beta subnits respectively, forming a polymer. 7. The fibrin polymer "hardens" by action of the enzyme glutaminase, which combines together the side chains of glutamine and lysine with a covalent bond. 8. Prothrombin must bind calcium in to be held near the site of the wound to be activated. Binding of calcium by prothrombin allows it to anchor itself to the phospholipid membranes derived from blood platelets after injury. At this site, prothrombin can be readily converted to thrombin because at the site of the injury are other enzyme that can activate prothrombin to thrombin. To enable prothrombin to strongly bind calcium, glutamate residues in it must be carboxylated (addition of a carboxyl group). This reaction is catalyzed by an enzyme that uses Vitamin K as a cofactor. 9. Compounds like coumarin or warfarin that block vitamin K sites on the enzyme act as "blood thinners", reducing the likelihood of blood clotting. 10. Removal of blood clots involves an enzyme called plasmin, which is synthesized as a zymogen called plasminogen. Plasminogen is converted to plasmin by tissue-type plasminogen activator (t-PA). t-PA can be extremely effective in initiating the cascade to dissolve the unwanted blood clot involved in stroke or heart attack.