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48 Cards in this Set
- Front
- Back
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What's an example of a reversible noncovalent modifiction?
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Allosteric
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What's an example of a covalent modification?
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Phosphorylation
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What are the characteristics of irreversible covalent modification? What's an example?
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Occurs once in the lifetime of a enzyme; can occur in extracellular space; does NOT require metabolic energy. An example: cleaving of proteases.
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What are the 3 serine digestive proteases made in the pancreas?
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Chymotrypsin; trypsin; elastase.
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What is the digestive Zn protease made in the pancreas?
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Carboxypeptidase.
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What is the aspartyl protease made in the stomach?
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Pepsin
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What is method for activating pancreatic serine proteases?
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1. Enteropeptidase is secreted in duodenum. 2) Enteropeptidase cleaves tyrpsinogen; now activated to Trypsin 3) Trypsin activates other pancreatic enzymes: elastase, carboxypeptidase. Causes cascade, and they activate chymotrypsin and lipase.
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How is chymotrypsin activated?
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Cleave chymotrypsinogen between residues 15 and 16. N-terminus still there, holding on by a disulfide link. Allows structures to come closer together to activate the active site. So everything is there, just not in the right orientation. Point of cleavage: not huge structural changes. Small changes that can lead to activation of active site.
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How do we turn off proteases once they've been cleaved? Remember, it's irreversible?
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Use a protease inhibitor enzyme.
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How does pancreatic trypsin inhibitor work?
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It's a small protein that binds to trypsin tightly on its active site. Binding is really tight. It happens because trypsin cleaves Lys residues, and it tries to cleaves PTI's lysine residue and instead gets screwed.
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What's a serpin?
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A serine protease inhibitor.
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Tell me about a1-antitrypsin.
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It's a serpin that inactivates elastase. Elastase is secreted by neutrophils as part of inflammatory process. We want this elastase restricted to where the infection is, so a1-antityrpsin turns it off.
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Tell me more about a1-antitrypsin. What if it doesn't work?
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If it doesn't work, then we make too much elastase. The excess elastase attacks alveolar lung walls and leads to emphysema.
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Tell me about cigarettes, a1-antitrypsin deficiency, and being heterogzygous for a1-antitrypsin deficiency.
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If you're heterzygous for mutation, cigarettes can cause a methionation (addition of one O) in the working copy of the serpin. This lowers serpins infinity for elastase dramatically and can lead to emphysema.
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What's a caspase?
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A cysteine protease that cleaves peptide bonds very specifically next to ASPartate residues. Hence the Caspase name. Critical for apoptosis. Made in zymogen form and then proteolytically cleaved.
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What's apoptosis?
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Programmed cell death. Necessary for many functions, especially embryogenesis. Helps get rid of injured cells and preserve cell numbers, and maintain the immune system.
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What are the two classes of caspase?
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Initiator and execution.
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What triggers an initiator caspase?
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External signals through death receptors, or internal signals like DNA or mitochondrial damage.
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What main thing does activation of initiator caspase do?
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Activate the execution caspases.
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How is inactive initiator caspase different structurally then active?
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Active is dimerized and self-cleaves itself @ aspartate molecules. Have 4 pieces.
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Break down caspase pathway for me again.
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1. Ligand binds to death receptor. Get a scaffold for autocatalytic activation of initiator caspase (cleaves itself @ Asp). Initiator caspase cleaves execution caspases directly.
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What are the two blood clotting pathways?
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Intrinsic and extrinsic.
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What are characteristics of the intrinsic blood clotting pathway?
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Covers 5 proteolytic rxn is is mediated by components found in the plasma.
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What are the characteristics of the extrinsic blood clotting pathway?
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Made of 4 proteolytic steps and includes factors found in tissues.
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In blood clotting pathway, where do the extrinsic and intrinsic pathways meet?
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@ the conversion of prothrombin to thrombin
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Almost all clotting factors in the blood clotting pathway are what type of protease? Which does NOT fall in this category?
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Serine proteases. Fibrin is NOT a serine protease.
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What's thrombin do?
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Cleaves fibrinogen to form fibrin.
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What does fibrin do?
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Polymerizes to form the actual clot.
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Tell me about fibrinogen.
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Very abundant; makes up 3% of plasma protein; formed from 3 pairs of polypeptide chains into long rod; has disulfide links. There are globular regions @ both ends and in the middle.
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Fibrinogen is soluble. How does it come out of soln to form fibers/clots?
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Electrostatics. In inactive form, both ends of the molecule are -4, and the middle is -12. Thrombin cleaves the -12 in the middle (a Glu and Asp), and now the ends will interact with the middle of other molecules, and we get a fiber. Get a half-staggered effect.
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How does thrombin activate fibrinogen?
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It cleaves very specifically certain Arg-Gly bonds. Changes electrostatics of the fibrinogen; becomes fibrin and can form fibers.
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Tell me about fibrin and its clots.
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It initially forms soft clots. These become hard clots courtesy of Factor 13 or fibrin-stabilizing factor.
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How does Factor 13 help convert soft clots to hard clots?
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Forms peptide bonds between Lys and Gln residues.
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What role does Vitamin K play in blood clotting?
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It recruits key clotting factors to platelets. It carboxylates (adds a carboxy group) to glutamate residues. Glutamate goes from -1 to -2. @ -2 it can chelate (bind) to Ca2+
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How does chelation of Ca2+ aid in blood clotting?
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Clotting factors + Ca2+ bind to the platelet phospholipids and the factors come in close contact with each other. This proximity (between factors and platelets) enhances proteolytic activation of the clotting factors --> faster response to injury.
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What's a platelet?
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Small, irregularly shaped clear cell fragments. If too many, we can get thrombosis (blood clots); too few, we get bleeding.
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What are warfarin and dicoumoral and how can they interfere with blood clotting?
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They are blood thinners that are Vitamin-K antagonists. Screws with the whole chelation/bringing factors closer together scheme. Slows response. Screw with localization of platelets.
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Tell me about von Willebrand Factor (vWF)
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vWF is found on the subendothelial layer. When a blood vessel is injured, platelets can localize to the subendothelial layer by working with vWF. The platelets will then release contents from granules to recruit other platelets to site of injury. Several clotting factors are attached to surface of platelets and accelerates activation of factors.
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What about Cofactor Va?
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It's a clotting factor that's on the surface of platelets. It has a binding site for prothrombin and Factor 10. Assembling these factors on the platelet surface makes enzymatic conversion more than 10,000 times faster.
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How does thrombin AMPLIFY feedback for blood clotting process?
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1. It activates fibrin. 2) It accelerates OTHER thrombin molecule activation by activating factors 5, 8, 11. 3) It stimulates release of F8 from vWF and activates platelet agreggation.
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How does thrombin INHIBIT feedback?
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1) Binds to a receptor on epithelial cells (thrombomodulin). 2) Binding activates protein C. 3) Protein C forms complex with Protein 2, prevents thrombin from cleaving fibrinogen 4) Complex also cleaves several factors and disables factors 5 and 8.
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How else is thrombin inactivated?
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Serpins related to a1-antitrypsin. Antithombin3 binds to heparin. The - heparin binds to Lys on antithrombin3 and induces allosteric change to enhance binding to thrombin. Once bound to thrombin, the heparin is released and activates other antithrombin 3 molecules.
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What is plasmin?
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A serine protease that dissolves the clots once they're no longer needed. Formed by cleavage of plasminogen. It cuts up fibrin clot into smaller peptides.
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What activates plasminogen?
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TPA. Plasminogen activators like TPA are also used as treatments for heart attacks and dissolving blood clots.
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What two factors (or lack of factors, that is), lead to hemophilia? Which one for type A? Type B?
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F8 and F9. Hemophilia A --> F8 mutation (very common). Hemophilia B --> 9
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What's happening in hemophilia?
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You have mutations or reduced expressions of F8 and F9. Both of these activated F10. If you can't activate F10, you won't get clotting.
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What kind of mutation is hemophilia?
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Sex-linked recessive.
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Tell me about factor 8.
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The activation and inactivate occur through proteolytic cleavage. Thrombin cleaves F8 on vWF; this allows it to form an active complex with F9 on a phospholipid surface of platelet. This Stimulates cleavage and activation of F9.
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