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87 Cards in this Set
- Front
- Back
Hb binds O2 at a _______ pH level (lungs) and releases O2 at a ______ pH level (tissues) Why? |
Higher Lower Lower, acidic pH strengthens the ionic interactions in the T-state (histidine gets protonated) |
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Heme is comprised of ...? (2) |
1. Protoporphyrin IX ring 2. Ferrous (2+) iron |
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What are the six bonds that Fe2+ forms in a heme? |
4 to the protoporphyrin ring 1 to a histidine side chain from helix F 1 to O2 |
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What is the main secondary structure found in Mb and Hb? |
alpha-helix |
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Lower Kd = ______ tightly bound ligand to protein |
more tightly bound |
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In which state is the Fe+ of heme evenly situated in the plane of the protoporphyrin ring? Higher or lower O2 binding affinity? |
Relaxed Higher |
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How many ionic bonds are present in the T-state of Hb? How many interchain / intrachain? |
8 6/2 |
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How does the concentration of CO2 affect binding affinity of O2 to Hb? |
Higher concentrations = lower O2 binding affinity Lower concentrations = higher O2 binding affinity |
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How does the concentration of CO affect binding affinity of O2 to Hb? |
Higher concentrations = higher O2 binding affinity Lower concentrations = lower O2 binding affinity |
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What protein is a strong regulator of O2 binding affinity, decreasing the affinity of Hb for O2? |
2,3-bisphosphateglycerate (BPG) |
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How does carbon dioxide lower Hb affinity for O2? (2) |
1. 23% of Co2 forms a non-covalent adduct (carbaminohemoglobin) with Hb 2. The conversion of CO2 to HCO3 and H+ acidifies the system, decreasing O2 binding affinity |
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How does CO poisoning affect Hb? |
CO binds Hb 250x more tightly than O2 and stabilizes the R-state, making it harder for Hb to offload CO2 |
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What disease state is caused by the oxidation of Fe2+ to Fe3+? What can cause it? |
Methemoglobinemia -Exogenous oxidizing drugs (benzocaine, dapsone), compounds containing nitrates or well water contaminated by nitrates |
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What happens to the tissue BPG levels at high altitude? |
They increase to increase the release of bound O2 in the tissues |
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What is the difference on the structural level between gamma Hb and beta Hb subunits? |
In gamma: 2 serine residues replace 2 histadine residues in the BPG binding pocket of the B subunit. Therefore, HbF has a lower affinity for BPG and higher affinity for O2 |
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What genetic defect leads to sickle cell disease? |
Glu6 -> Val6 in B-globin chain of hemoglobin |
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What defect is seen in Hemoglobin C disease? More or less severe than sickle cell? |
Glu6 -> Lysine Less severe |
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What are HbS prone to that HbA are not? Under what conditions? |
They self-assemble into strands and fibers Caused by conditions that promote the deoxy form: exercise, high altitudes, hypoxic conditions |
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What drug is used to treat sickle cell? Mechanism? |
Hydroxyurea Promotes the expression of fetal Hb, which replies the abnormal HbS B-globin allele in some hemoglobin molecules. HbF cannot self-assemble into strands/fibers, and prevents the formation of sickle cells |
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What are the 2 types of alpha-globin genes? When are they seen? |
alpha and zeta Alpha: almost always Zeta: only in embryonic Hb |
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What are some genetic causes of Methemoglobinemia? |
-Mutations in NADH-cytochrome B5 reductase -Mutations in a- and b-globin chains near the heme iron Genetic deficiencies of enzymes that reduce the levels of NADH in the cell (pyruvate kinase) |
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What is a treatment for Methemoglobinemia? |
IV infusion of methylene blue |
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What is the genetics of thalassemias? |
Autosomal recessive |
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Which Thalassemia is most common in Mediterraneans? |
Beta |
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On which chromosomes are the alpha and beta-globin genes clustered? |
16 (alpha) 11 (beta) |
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Expression of globin genes is regulated by what? |
LCRs Locus control regions |
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A complete absence of B-globin expression is known as? About 50% absence? |
Complete = B0-thalassemia Half = B+-thalassemia |
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What can cause B+-thalassemia? |
Being het for a mutation in the B-globin locus, or having a mutation in the control region |
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What is the result of a-thalassemia(-) with no a-globin expression? |
Still births |
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What is thrombosis? (2) |
1) aggregation of platelets 2) formation of an insoluble fibrin clot |
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What does the blood clotting cascade require? |
Ca++ |
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What cross links fibrin? |
Factor XIII |
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What is the initiator of the clotting response (released from the damaged sub endothelial layer of blood vessels)? |
von Willebrand Factor |
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What forms fibrin by cleaving fibrinogen? |
Thrombin |
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What residues in the coagulation factors bind phospholipids on platelet membranes to localize the clotting? |
y-carboxyglutamate |
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What is the first platelet integrin to bind the injury? What does it bind? The second? What does it bind? |
1st: GPIa/IIa, binds collagen 2nd: GPIIb/IIIa, binds vWF and fibrinogen |
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Platelet activation releases what factors from the cell? |
1. ADP (stimulates platelet aggregation) 2. BCC factors: Factors V and XIII and fibronigen 3. Ca++ 4. Platelet factor 4: binds heparin 5. Growth factors (initiate migration and proliferation of wound healing cells) 6. Serotonin (vasoconstrictor) |
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Platelet activation stimulates synthesis of ________, which is a vasoconstrictor & activates GPIIb/IIIa on cell surface. What drug inhibits this? |
Thromboxane A2 low dose aspirin |
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Where does vWF come from? What are its 2 major roles? |
-vWF is present in the subendothelial space and secreted from platelets 1. Activates platelets via the GP1b R in the sub endothelial space 2. stabilizes Factor VIII in circulation |
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Hemophilia A is characterized by lack of what? |
Factor VIII |
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What is a zymogen? The zymogens of the BCC become... |
A polypeptide chain that only displays biological activity after it has been chemically altered, usually by proteolytic cleavage -Serine proteases & protein cofactors |
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Which factors are serine proteases that are activated by cleavage? |
VII, XI, IX, X, prothrombin, Protein C (all have a after once activated) |
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What is the associated factor for Factor VII? |
Tissue Factor (Factor III) |
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What is the associated factor for Factor IXa? |
Factor VIIIa |
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What is the associated factor for Factor Xa? |
Factor Va |
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What is the associated factor for Factor IIa (thrombin)? |
Thrombomodulin |
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What is the associated factor for Protein Ca? |
Protein S |
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What is the extrinsic pathway for the BCC? |
Damaged tissues present Tissue Factor III to circulating factor VII -> autocatalyzes to factor VIIa -> activates factor X to Xa
VIIa -> activates IX to IXa in the intrinsic pathway |
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What is the intrinsic pathway for the BCC? |
XI to XIa -> IX to IXa -> activates X to Xa |
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What is the result of X activation to Xa? |
Thrombin activation |
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How can thrombin augment its own activation? |
By converting factors V, VIII, and XI into activated cofactors |
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What is the common pathway? |
X to Xa + Va -> prothrombin to thrombin |
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How does thrombin cross-link fibrin? |
Thrombin activates Factor XIII to XIIIa XIIIa catalyzes a transamidation reaction between Glutamine and Lysine side chains |
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Which coagulation factors are post-translationally modified with y-carboxyl groups to increase their ability to bind calcium? |
Factors II, VII, IX, X, and Protein C |
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What is a required cofactor for y-carboxylation? |
Vitamin K |
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What contributes to the thromboresistance of normal vascular endothelium? (3) |
1. Endothelial cells are highly negatively charged 2. They synthesize Prostaglandin I2 and NO (vasodilators and inhibitors of platelet aggregation) 3. They synthesize thrombomodulin and heparin sulfate, which inhibit thrombin |
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What can reversibly inhibit Factor Xa? What does it also inhibit? |
Tissue Factor Pathway Inhibitor (TFPI) TFPI-Xa complex can inhibit FVIIa-TF complex |
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What naturally occurring inhibitory proteins are present in the plasma at high concentration? They inhibit serene proteases |
Serpins |
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What serpin controls the activity of Thrombin and other serine proteases? |
Antithrombin III (ATIII) |
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How does heparin accelerate the rate of Thrombin inactivation? |
BInds lysine residues on ATIII and accelerates its rate of Thrombin binding by making its arginine residue more readily available for interaction with thrombin |
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What is the pathway of thrombin's anti-thrombotic effects? |
Thrombin binds the endothelial cell R thrombomodulin -> alters function of Thrombin and allows Thrombin to activate Protein C -> protein Ca & cofactor Protein S suppress the BCC by cleaving & deactivating Factor VIIIa and Va by proteolytic cleavage |
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Protein Ca stimulates endothelial cells to increase secretion of ________, which reduces platelet aggregation |
prostaglandin PGI2 |
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What type of factor Va is resistant to inactivation by Protein Ca/Protein S? What is the result? |
Factor V Leiden Hypercoagulability |
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What serine protease degrades the fibrin in a clot? |
Plasmin |
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What protein converts plasminogen to plasmin? What proteins inhibits plasmin? |
Activators: tPA: tissue plasminogen activator scu-PA (urokinase) Streptokinase: bacterial protein
Inhibitors: -alpha-2-antiplasmina: inhibits plasmin activity -Plasminogen activator inhibitor (PAI-1): inhibits tPA |
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What cells produce immunoglobins? |
B cells |
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What is a foreign molecule that is selectively bound by antibodies? |
Antigen |
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What is the molecule that induces antibody production? |
Immunogen |
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What is the small region of a larger molecule that elicits the production of a specific antibody? |
Antigenic determinant / epitope |
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What types of bonds hold the heavy chains to each other, and heavy to light chains? |
Disulfide |
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What domains exist within the heavy chains? |
CH1-CH3 (constant), VH (variable) |
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What are the 2 types of light chains? What domains exist within light chains? |
Lambda or kappa CL (constant) and VL (variable) |
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Where is the antibody cleaved by papain? |
Between CH1 and CH2 (cleaves the V from the Y), into Fc (heavy only) and Fab (light chain and heavy chain VH and CH1) |
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What is the basic shape of an IgA? Heavy chain? |
Dimer Alpha |
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What is the basic shape of an IgM? Heavy chain? |
Pentamer u (mu)
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Each individual constant and variable domain in an antibody is an example of ________ |
Supersecondary structure |
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Antibodies are comprised mostly of what type of secondary structure? |
B-sheet/ B-sandwich |
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What is the arrangement of beta strands in the constant domains? What is the arrangement of beta strands in the variable domains? |
4-3 5-4 |
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What are the specific antigen binding sites within the variable domain? How many are there? |
Complementarity Determining Regions (CDRs) 3/variable region, 12 total |
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What proteins other than antibodies have an immunoglobin fold structural motif? |
Fibronectin and cell adhesion molecules (CAMs), T-cell receptor and MHCs |
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What antibody-based technique is used to investigate the interactions between protein and DNA in the cell? |
ChIP |
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What is a cancer from a plasma cell called? What are the symptoms? |
Myeloma CRAB: Ca++, renal failure, anemia, bone lesions |
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What is used to select for fused mouse spleen/myeloma cells in culture? |
HAT medium: only cells with HGPRT enzyme (from spleen cells) can grow |
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What type of antibody has a variable domain from mouse with the remainder from human origin? Suffix? |
Chimeric Ends in -ximab |
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What type of antibody has the CDRs from mouse with the remainder from human origin? Suffix? |
Humanized Ends in -zumab |
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What type of antibody is entirely human? Suffix? |
Fully human Ends in -mumab |
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What is the suffix for a fully mouse antibody? |
-momab |