Term
| Solubility of gases in water |
|
Definition
| The more polar a gas, the more soluble |
|
|
Term
|
Definition
| Protoporphyrin IX / Ferrous ion (Fe2+) / six bonds = 4 protoporphyrin ring, 1 to the H from helix F, 1 to O2/ |
|
|
Term
| Myoglobin - Hemoglobin Structural Differences |
|
Definition
| Mb is a monomer, with a single protein and a single heme group. On the other hand, Hb is a heterotetramer. |
|
|
Term
| Myoglobin - Hemoglobin Structural Similar |
|
Definition
There are four subunits in total (see boxed insert): two α-globin subunits (in grey; α1 and α2) and two β-globin subunits (in blue; β1 and
β2). Each subunit has a central heme group (shown in red). The α-globin and two β-globin gene are evolutionally related genes. |
|
|
Term
| Tense and Relaxed States for Hb |
|
Definition
In the R state, the Histidine is positioned such that the Fe+2
is evenly situated in the plane of the
protoporphyrin ring. This conformation has a higher affinity for binding O2. In the T state, the
Histidine is positioned such that it pulls the Fe+2 out of the plane of the protoporphyrin ring. This
conformation has a lower affinity for binding O2. |
|
|
Term
| Why the T state so tense? |
|
Definition
| The answer lies in eight ionic bonds that exit in the T state. Six of these ionic bonds are interchain ionic bonds between different subunits. Two are intrachain ionic bonds. These ionic bonds hold the four subunits in the T state, which is rigid and positions the Histidine residues such that they pull the Fe+2 out of the plane of the protoporphyrin ring. |
|
|
Term
|
Definition
| The more O2 molecules bound, the less ionic bonds restricting the subunits, the more the histidine can move the Fe+2 into the plane of the protoporphyrin ring, and the greater the affinity Fe+2 has for it ligand O2. |
|
|
Term
| What is significant about the Relaxed state? |
|
Definition
The relaxed state has a different conformation than I state that holds the histidine side chains such that they keep the Fe+2 in the plane of the protoporphyrin ring. This
position creates a higher affinity of the Fe+2 for O2. |
|
|
Term
| Acidity's effect on binding |
|
Definition
| The more acidic the pH, the lower the affinity Hb has for O2. This would shift the O2 binding curve to the right. The more basic the pH, the higher the affinity Hb has for O2. This would shift the O2 binding curve to the left. |
|
|
Term
| The concentration of carbon dioxide (CO2) |
|
Definition
| The higher the CO2 concentration, the lower the affinity Hb has for O2. This would shift the O2 binding curve to the right. The lower the CO2 concentration, the higher the affinity Hb has for O2. This would shift the O2 binding curve to the left. |
|
|
Term
| The concentration of carbon monoxide (CO) |
|
Definition
| The higher the CO concentration, the higher the affinity Hb has for O2. This would shift the O2 binding curve to the left. |
|
|
Term
| The concentration 2,3-bisphosphoglycerate (BPG) |
|
Definition
| BPG decreases the affinity of Hb for O2, and shifts the binding affinity curves to the right. |
|
|
Term
| Mechanism of binding affinity change and pH shift |
|
Definition
| the lower more acidic pH favors ionization and strengthens the ionic interactions of the T state. This would lower the O2 binding affinity |
|
|
Term
| The three mythical fates of CO2 that enters the plasma from tissues |
|
Definition
| 10% of the CO2 remains dissolved and goes to the lung in the plasma / 23% reversible, non-covalent adduct with 4 amino terminal subunits of hemoglobin / ~70% converted to bicarbonate (remember the Cl-bicarbonate antiport) |
|
|
Term
| What enzyme is responsible for bicarbonate transformation? |
|
Definition
|
|
Term
|
Definition
| CO binds to Hb ~250 times more tightly than does O2. CO also stabilizes the R state of Hb, which shifts the binding curve to the left, and prevents O2 from being off loaded and delivered to the tissues. Since it binds Hb tightly, unless treated the CO remains bound to the Hb and exerts is effect. |
|
|
Term
| Carbon Monoxide Poisoning |
|
Definition
| Exposure to CO is very poisonous. The earliest symptoms of CO poisoning are non-specific and readily confused with flu-like syndromes (headache, nausea, vertigo). High concentrations of HbCO (50-60%) lead to seizures, coma and death. |
|
|
Term
|
Definition
| Caused by the oxidation of Fe+2 to Fe+3. This forms methemoglobin (MetHb). Oxygen is not carried by MetHb, so like CO, the oxidation of Fe+2 and the creation of too much MetHb can be deadly. |
|
|
Term
| What causes Methemoglobinemia? |
|
Definition
| MetHb can be caused by exposure to exogenous oxidizing drugs (benzocaine, dapsone), increasing the rate of Fe+2 oxidation ~1000-fold. Ingestion of compounds containing nitrates (bismuth nitrate) or well water contaminated by nitrates can also cause methemoglobinemia. Infants are particularly susceptible to nitrates ingested in drinking water, and can lead to blue-baby syndrome. |
|
|
Term
| What percent of O2 is released due to 23 BPG |
|
Definition
| At sea level our bodies maintain BPG levels at ~5 mM. Hb is ~95% saturated with O2 in the lungs and ~57% saturated in the tissues. BPG therefore promotes the release of ~38% of the bound O2 to the tissues. |
|
|
Term
| 2,3 BPG and altitude differences |
|
Definition
| Upon going up, a person has same amount of BPG (5mM), but O2 concentration has changed / After a while the body increases the amount of BPG (8 mM) |
|
|
Term
|
Definition
| Fetal Hemoglobin has two Gamma subunits rather than two Beta. Gamma subunits have 2 serine residues to replace histidine. Fetal Hb has less affinity for 2,3 BPG, thus has a HIGHER affinity for O2 ==> duh |
|
|
Term
| What gene is defective in Sickle Cell Anemia? |
|
Definition
|
|
Term
| Describe the mutation in Sickle Cell anemia? |
|
Definition
| Point mutation to 6th amino acid / Glu to Val |
|
|
Term
|
Definition
| Point mutation to 6th amino acid / Glu to Lys Less severe than Sickle cell anemia |
|
|
Term
| What are the sickles in sickle cell anemia? |
|
Definition
| HbS when in its deoxy form (hypoxic conditions) crystal filaments |
|
|
Term
|
Definition
| Drug that treats Sickle Cell A / Promotes the expression of fetal hemoglobin which replaces the ineffective HbS / It can also bind to growing crystal fiber strands, making less sickle cells produced |
|
|
Term
|
Definition
A sickle cell crisis can be quite painful, so one aspect of any treatment regimen includes pain management.
Blood transfusions are used to treat the anemia, although iron overloading is a side effect. Prophylactic
antibiotics are used to prevent infection. Bone marrow transplants are also used for patients with stroke,
recurrent acute chest syndrome, and chronic unrelieved pain. |
|
|
Term
| α (alpha)-globin genes (Types) |
|
Definition
| α and ζ (zeta), both expressed from within a clustered locus control region (LCR). The ζ chain is expressed very early in embryonic development and is synthesized in the yolk sac. The α chain is expressed and is the main α-globin during fetal development and throughout life. |
|
|
Term
|
Definition
| β, γ (gamma), δ (delta) and ε (epsilon). Like the α and ζ genes, the human β-globin genes are also expressed from within a clustered LCR. The β chain is the major allele expressed and is found in adult Hb (HbA). The γ chain is expressed during fetal development and is found in fetal Hb (HbF). The δ chain is expressed in a second type of adult Hb (HbA2), comprising only a small fraction of the total Hb expressed in adults. Finally, the ε chain is expressed in the embryonic yolk sac, and with the ζ chain, constitutes the embryonic Hb (HbE). |
|
|
Term
| Expression of the Human Globin Genes During Fetal Development to the First Year of Life |
|
Definition
| Look at chart! Look at it |
|
|
Term
| Methemoglobinemia (cause - non genetic) |
|
Definition
the oxidation of Fe+2 to Fe+3 inhibits the ability of Hb to deliver O2 to the tissues / can be caused by certain chemicals (e.g.,
nitrates and drugs), and reactive oxygen intermediates involved in biosynthetic pathways / |
|
|
Term
| Methemoglobinemia (cause - genetic) |
|
Definition
certain mutations in the α- and β-globin chains near the heme iron can lead to enhanced formation of methemoglobin (met-Hb). These mutations have an autosomal dominant inheritance pattern / Genetic deficiencies of enzymes that reduce
the levels of NADH in the cell (eg, pyruvate kinase) can also cause methemoglobinemia |
|
|
Term
| NADH-cytochrome B5 reductase |
|
Definition
| Normally reoxidizes met-Hb back to Hb / Deficiencies in this enzyme can also result in methemoglobinemia. |
|
|
Term
| Treatment of Methemoglobinemia |
|
Definition
| The intravenous infusion of methylene blue can reduce the Fe+3 in the heme group back to Fe+2 |
|
|
Term
|
Definition
Thalassemia is defined as a
mutation, either deletion or point, that diminishes or eliminates the production of one of the two chains of
hemoglobin. Failure to express the functional globin proteins causes anemia and reduces the blood’s ability to carry oxygen. |
|
|
Term
| Locus Control Regions (LCRs |
|
Definition
Where the expression of the genes is
regulated |
|
|
Term
| Where are the alpha and beta globin genes located? |
|
Definition
| chromosomes 16 and 11, respectively |
|
|
Term
| β°-thalassemia (β-thalassemia Major or Cooley’s Anemia) |
|
Definition
Absence of β-globin expression (mutants in both copies of the β-globin gene) /This results in ineffective erythropoiesis, and these patients present in the first year of life with severe
microcytic hypochromic anemia. In addition to the anemia, the buildup of iron in the heart and other organs can
result in heart failure as early as the second or third decade of life |
|
|
Term
|
Definition
If only one allele is affected (the patient is heterozygous for the mutation), there is approximately a 50%
reduction of expression from the β-globin locus |
|
|
Term
|
Definition
results from mutations in the control
regions (either the LCR or the immediate upstream promoter region) / Deletions obliterate the
enhancer sequences in the LCR, needed for high level
transcription. As a result, in β+-thalassemia there is
reduced expression of β-globin. |
|
|
Term
|
Definition
| In α-Thalassemia, the severity of the disorder is dependent upon the level of reduction of α-globin expression, In α-Thalassemia(-), there is essentially no α-globin expressed (analogous to β°-Thalassemia). This results in still births. In slightly milder situations, where α-globin expression is reduced to about 25% of normal, the excess β-globin chains form unstable HbH, which has abnormal O2 dissociation curves and less effective O2 delivery to the tissues and a microcytic anemia occurs. If there is a 50% reduction of α-globin, a more mild microcytic anemia results. |
|
|
Term
| What kind of cells derive platelets? |
|
Definition
|
|
Term
| How do platelets attach to points of injury? |
|
Definition
| Adhesion involves the attachment of platelets to the subendothelial cells, and the collagen connective tissues (Figure 2). Blood vessel injury exposes the platelets to collagen, and vWF, synthesized from endothelial cells, megakaryocytes, and platelets. Platelet membrane glycoproteins (GPs) bind to collagen through interactions with vWF, causing the platelets to adhere to the subendothelium. |
|
|
Term
| Mechanism of platelet attachment? |
|
Definition
| Interaction of GPIa/IIa (integrin α2β1) to the collagen (1) causes the platelet to change from a flat disc to a spherical cell. The platelet extends pseudopods, promoting platelet to platelet interactions. The binding of vWF by GPIb (2) causes changes in the platelet membrane, exposing GPIIb/GPIIIa (integrin αIIbβ3), -binding sites (3) to fibrinogen and vWF. |
|
|
Term
|
Definition
| vWF is present in the subendothelial space and is secreted from platelets, where it is involved in platelet activation. Circulating forms of vWF produced by endothelial cells bind to and stabilize inactive Factor VIII in circulation. |
|
|
Term
|
Definition
| In the absence of vWF, Factor VIII is rapidly degraded. The most common cause of genetic bleeding disorders (1:100 live births) is a deficiency in vWF. This is an autosomal recessive disorder. |
|
|
Term
| Hemophilia A (or classic hemophilia) |
|
Definition
| X-linked disorder characterized by a lack of Factor VIII. |
|
|
Term
| What can activate platelets? |
|
Definition
| ADP (platelet to platelet contact) and Serotonin (creates Thromboxane A2 - vasoconstrictor... reduces blood to injury) and Growth Factor (Platelet derived growth factor... proliferation of vascular cells) |
|
|
Term
|
Definition
a
vasoconstrictor that activates more GPIIb/GPIIIa. Activation recruits
more platelets to the site, which also degranulate. |
|
|
Term
| Low dose aspirin and clotting |
|
Definition
| Low-dose aspirin inhibits the synthesis of Thromboxane A2 by platelets. This is why aspirin increases blood clotting time. |
|
|
Term
| What will activated platelets bind to? |
|
Definition
|
|
Term
| What does platelet activated fibrinogen do? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
Cleavage of Fibrinogen by Thrombin
produces Fibrin monomers. The monomers polymerize / This is considered a “soft” clot because the Fibrin
monomers are not cross-linked.
together with platelets to form a “soft clot”. |
|
|
Term
| Associated Factor of Factor VII |
|
Definition
|
|
Term
| Associated Factor of Factor IXa |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
| damaged tissues present tissue Factor (III) to circulating Factor VII. Factor VII autocatalyzes its own activation to Factor VIIa. Factor VIIa then activates Factor X (to Xa). |
|
|
Term
| All cascade reactions require what co-factors? |
|
Definition
| All of these conversions require access to platelet membranes (PL) and calcium. PL is used as a scaffold for the activation reactions to occur. The protein cofactors VIIIa and Va also serve as assembly sites for enzyme– cofactor complexes on the platelet surface, thereby accelerating and localizing the reaction. |
|
|
Term
|
Definition
VIIa also activates Factor IX (to IXa) in the intrinsic pathway. Factor IXa, as part of the intrinsic pathway, also activates Factor X. Therefore, Factor Xa is activated (from X) by both the extrinsic and intrinsic pathways. All
of these conversions require access to platelet membranes (PL) and calcium. PL is used as a scaffold for the activation reactions to occur. The protein cofactors VIIIa and Va also serve as assembly sites for enzyme– cofactor complexes on the platelet surface, thereby accelerating and localizing the reaction. The final result is Thrombin activation. Thrombin can also augment its own activation by converting Factors V, VIII, and XI into activated cofactors. This stimulates additional platelet degranulation. The initial activation of Prothrombin is slow because the activator cofactors, VIIIa and Va are present only in small amounts. However,Protease Associated Factor
Factor VII Tissue Factor Factor IXa Factor VIIIa Factor Xa Factor Va
Factor IIa (thrombin) Thrombomodulin Protein Ca Protein S once a small amount of Thrombin is activated, it accelerates its own production (>100,000 fold) by cleaving
Factors V and VIII to their active forms. Note that these factors are in the intrinsic pathway. The intrinsic
pathway is thought to sustain the coagulation response initiated by the extrinsic pathway. |
|
|
Term
|
Definition
The major substrate of Thrombin is Fibrinogen, which is hydrolyzed to form Fibrin monomers. These monomers undergo spontaneous polymerization to
form the fibrin clot. |
|
|
Term
| Cross linking a "soft" clot |
|
Definition
| Cross-linking requires Factor XIIIa, which is activated by Thrombin cleavage of Factor XIII. Factor XIIIa catalyzes a transamidation reaction between Glutamine and Lysine side chains on adjacent Fibrin monomers, creating a strong network of fibers that is resistant to mechanical and proteolytic damage |
|
|
Term
| Transamidation of which amino acids in fibrin hard clots |
|
Definition
|
|
Term
So what attracts these coagulation
factors to the site of injury? |
|
Definition
Tissue injury exposes new phospholipid
molecules that are covered with
Ca+2. Certain of the coagulation
factors (II, VII, IX, X and Protein C)
are posttranslationally modified with
γ-carboxyl groups to increase their
ability to bind calcium and localize
on surfaces at the site of injury. |
|
|
Term
| Gamma-carboxylation co factor |
|
Definition
|
|
Term
| How is the antithrombotic process regulated? |
|
Definition
| Endothelial cells are highly negatively charged, a feature that may repel the negatively charged platelets. Endothelial cells also synthesize Prostaglandin I2 (PGI2) and nitric oxide, both vasodilators and powerful inhibitors of platelet aggregation. Endothelial cells also synthesize two cofactors that each inhibit the action of Thrombin: thrombomodulin and heparin sulfate. |
|
|
Term
|
Definition
| potentiates the activity of Antithrombin III, but not as efficiently as heparin. The inactivation of Thrombin is accelerated by heparin sulfate present on the endothelial cell surface. |
|
|
Term
| Tissue Factor pathway inhibitor |
|
Definition
| (TFPI) is a single-chain polypeptide which can reversibly inhibit Factor Xa (Xa) and its downstream substrate Thrombin (Factor IIa, Figure 8). While Xa is inhibited, the Xa-TFPI complex can subsequently also inhibit the Factor VIIa-Tissue Factor complex in the extrinsic pathway. TFPI contributes significantly to the inhibition of Xa in vivo, despite being present at low concentrations. |
|
|
Term
|
Definition
| Serine Protease Inhibitors(Serine Protease Inhibitors) are a group of naturally occurring inhibitory proteins that are present in the plasma at high concentration. At least eight major inhibitors have been found that share a common mechanism of action and inhibit proteases involved in coagulation and fibrinolysis. |
|
|
Term
|
Definition
Serpin - controls thrombin - irreversibly inactivates one molecule of Thrombin through reaction
of an arginine residue in ATIII with the active-site serine residue of Thrombin. |
|
|
Term
|
Definition
| ATIII–Thrombin complex formation is markedly enhanced in the presence of heparin. Heparin binds to Lysine residues on ATIII and dramatically accelerates its rate of Thrombin binding. This is because of an allosteric alteration in ATIII such that the position of the critical arginine residue of ATIII is more readily available for interaction with Thrombin. |
|
|
Term
| What other protease factors does heparin slow down? |
|
Definition
The ATIII–heparin complex also can inactivate the serine protease Factors
XIIIa, XIa, IXa, and Xa, but has no effect on Factor VIIa or activated Protein C |
|
|
Term
|
Definition
| Thrombomodulin alters the clotting function of Thrombin, and allows Thrombin to instead activate Protein C. Once activated, Protein C has anticoagulant effects. Protein Ca, and its cofactor Protein S (PS), suppress the activity of the coagulation cascade by deactivating cofactors Factor VIIIa and Va by proteolytic cleavage. |
|
|
Term
|
Definition
| A variant of Factor V, referred to as Factor V Leiden, is incapable of being inactivated by this complex. If Factor Va cannot be inactive efficiently, then Factor Xa will convert more Prothrombin to Thrombin, and more thrombosis will occur. |
|
|
Term
| hypercoagulability disorder, or Thrombophilia |
|
Definition
| Factor V Leiden / If Factor Va cannot be inactive efficiently, then Factor Xa will convert more Prothrombin to Thrombin, and more thrombosis will occur. |
|
|
Term
|
Definition
| Serine protease plasmin / Plasmin is activated by proteolytic cleavage from its inactive zymogen precursor, plasminogen. Plasminogen is a circulating serum protein that has a high affinity for Fibrin. This promotes incorporation of plasminogen at the site of developing clots. |
|
|
Term
|
Definition
| Such activators include Tissue Plasminogen Activator (tPA) and Urokinase (SCU-PA, single chain urokinase-type plasminogen activator). Streptokinase is a bacterial protein that happens to bind Plasminogen, and triggers a conformation change in Plasminogen that enables its autocatalysis to Plasmin. |
|
|
Term
| Negative regulators of Fibrinolysis |
|
Definition
These regulators either prevent the conversion of Plasminogen to Plasmin, or inhibit the active Plasmin. Plasminogen activator inhibitor (PAI-1) inhibits tPA, thereby preventing the conversion of Plasminogen to active Plasmin.
α2-antiplasmin inhibits Plasmin activity. |
|
|
Term
| At the clot surface... conversion of Plasminogen to Plasmin by Plasminogen activators |
|
Definition
| the activated Protein C complex, in addition to turning off the coagulation cascade, also stimulates the release of t-PA, and simultaneously inactivates PAI-1. Plasminogen activator release leads to Plasmin formation in the circulation. |
|
|
Term
| Circulating Plasmin... conversion of Plasminogen to Plasmin |
|
Definition
| circulating Plasmin is rapidly inactivated by binding with α2-antiplasmin. Clot-bound Plasmin is not efficiently inactivated by α2-antiplasmin. |
|
|
Term
|
Definition
three constant domains (CH1-CH3) and one variable domain (VH). The constant domains will be identical within each class of antibody (IgA, IgD, IgE, IgG and IgM), but will vary between each class. The heavy chain
therefore defines the class of immunoglobulin. The light chains can be one of two types: lambda (λ) or kappa (κ), and both contain constant (CL) and variable (VL) regions. |
|
|
Term
|
Definition
| A protease that cleaves between CH1 and CH2 of heavy chain. |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
| Supersecondary Structure of Constant domain |
|
Definition
| The yellow (or blue) β-strands are held together by virtue of the hydrogen bonds in an antiparallel arrangement. The yellow β-strands are held to the blue β-strands by virtue of hydrophobic interactions between the R groups of the two adjoining strand surfaces (yellow to blue). This supersecondary structure is referred to as an immunoglobulin fold, or a β-sandwich. |
|
|
Term
| Complementarity Determining Regions |
|
Definition
| Regions of the antibody that are complementary to the epitope. / |
|
|
Term
| What other proteins possess the immunoglobulin fold? |
|
Definition
| Fibronectin, Cell adhesion molecules, T cell receptors, and Major Histocompatibility Complex (MHC) |
|
|
Term
| Basic Antigen Binding Site |
|
Definition
| the heavy and light chain hypervariable CDR loops are located at the extreme end of the immunoglobulin structure (Figure 8). Note that there are three loops from the light chain (L1-L3) and three loops from the heavy chain (H1-H3). They form a cleft or pocket, which is where the antigen will bind. |
|
|
Term
|
Definition
Myelomas are cancer cells from plasma cells, a subset of B lymphocytes that secrete immunoglobulins. Symptoms include elevated Ca2+, renal failure, anemia, and bone lesions (CRAB). Patients with myeloma have high concentrations of monoclonal antibody (M protein) in their serum and secrete monoclonal light chains
called Bence Jones protein in their urine. |
|
|
Term
|
Definition
| Also note that all of the antibodies listed here contain the ending “–mab”. |
|
|
