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78 Cards in this Set
- Front
- Back
Hemoglobin
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-oxygen carrier in blood
-tetramers with quaternary structure (oligomer) -each of the 4 peptide chains is bound to a heme group -heterotetramer circulating in RBCs |
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Myoglobin
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-serves as a reserve supply of O2 in muscles
-facilitates movement of oxygen within muscles -composed of a single polypeptide chain & one heme group -a monomer in muscle cells |
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Heme Group
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-consists of an organic part, protoporphyrin IX, and an iron atom
-porphyrins contain four pyrolle rings linked by four CH groups (methene bridges) |
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Protoporphyrin IX
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-has 4 methyl, 2 vinyl, & 2 propionic acid side chains attached to a tetrapyrolle ring
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Porphyrins
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-found in nature
-are compounds in which side chains are substituted for the 8 hydrogen atoms at carbons numbered 1-8 in the pyrolle rings |
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Iron atom binds to...
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-the four nitrogen atoms (1-4 coordination positions) in the center of the protoporphyrin ring
-iron can form 2 more bonds; one on each side & perpendicular to the heme plane -these are termed the 5th & 6th coordination positions |
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Ferrous
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-in the 2+ oxidation state
-heme -ferroprototporphyrin --> ferrohemoglobin -only ferrohemoglobin can bind oxygen |
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Ferric
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-in the 3+ oxidation state
-hemin -ferriprotoporphyrin --> ferrihemoglobin (aka methemoglobin) -cannot bind oxygen |
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Polypeptide Chain
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-polypeptide chain for myoglobin --> composed of 153 AA
-hemoglobin --> composed of 2 alpha (or alpha-like) & 2 non-alpha chains -each polypeptide is the product of a separate gene & is called a globin chain |
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Golbin Produced During Development
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-Adult (HbA1) --> alpha2beta2
-Adult (HbA2) --> alpha2delta2 -Fetus (HbF) --> alpha2gamma2 -Embryo (Hb Gower 1) --> xi2epsilon2 -Embryo (Hb Gower 2) --> alpha2epsilon2 -Embryo (Hb Portland) --> xi2gamma2 -Xi only produce during 2st trimester of prenatal development --> replaced by alpha -epsilon only produced during first trimester |
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Hb Barts-Hydrops Fetalis Syndrome
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-increased levels of Hb Portland are found in cord blood of infants with alpha thalassemia and who have whats called Hb Barts-Hydrops Fetalis Syndrome
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Appearance of Fetal Hemoglobin (alpha2gamma2)
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-coincides with shift in site of erythropoiesis from yolk sac to liver & spleen
-alpha & gamma chain synthesis predominates after first 10-12 weeks of fetal development |
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Beta Chain Appearance
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-shows up near time of birth (can be seen as early as 6-8 weeks though)
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Chain synthesis during first 3 months after birth
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-Beta synthesis rapidly increases as gamma synthesis ceases
-by 6 months, beta chain synthesis reaches its max, and gamma goes does to 1% |
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Delta Chain Synthesis
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-begins late in 3rd trimester
-gradually increases during 6-12 months after brith until it reaches max adult level of 2.5% |
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HbA1c
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-formed by the post-translational modification of HbA
-levels are significantly elevated in patients with diabetes mellitus whose blood glucose levels are not well-controlled -formed by non-enzymatic addition of glucose (glycation) to the N-terminal alpha amino group of each beta chain an Amadori rearrangement forms stable adduct (aldimine --> ketimine) -measure of long term glucose levels in diabetics |
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3-D structure of a single globin polypeptide chain
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-about 75% of the chain is folded in right handed alpha helical conformation
-the inside consists almost entirely of non-polar residues -the heme group lies within a non-polar crevice within the chain |
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Structure of polypeptide chains
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-places heme in an environment where is can carry oxygen reversibly
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Proximal & Distal Histidine
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-There is a proximal and a distal His in the chain of hemoglobin
-Oxygen comes in and binds near the distal His |
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Quaternary Structure
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-hemoglobin is a globular protein
-the 4 polypeptide chains are bound by hydrogen bonds, salt linkages, & hydrophobic bonds -heme groups are located in crevices near the exterior of the molecule (1 in each subunit) -little interaction between 2 alpha & 2 beat chains -hemoglobin transports H+ & CO2 in addition to O2 -binding of these molecules is controlled by allosteric interactions |
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Required Physiological Properties of Hemoglobin
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1) Great Solubility (34% or 5mM)
a) spherical shape b) polar groups on surface of molecule 2) Transport larege quantities of O2 (18-20mL of O2 / 100 mL of blood) 3) Uptake & release of O2 at appropriate partial pressures of O2 a) saturated with O2 in lungs b) release sufficient amounts of O2 in tissue 4) Good Buffer |
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Oxygen Transported in Blood in 2 Ways
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1) as O2 in solution
2) in reversible chemical combination with hemoglobin of erythrocytes (each Hb can carry 4 O2) |
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Oxyhemoglobin
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-Hb combined with O2
-iron remains Fe2+ -oxyhemoglobin can reversibly lose O2 to form deoxyhemoglobin (iron remains Fe2+) |
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Oxygen Dissociation Curves
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-hemoglobin --> sigmoidal curve (due to cooperative binding --> binding of one heme facilitate binding of more heme)
-myoglobin --> hyperbolic curve - |
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Affinity for O2
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Cyt Oxidase > Mb > Hb
-characterized by p50 -Myoglobin p50 = 1-5 mm Hg (torrs) -Hemoglobin p50 = 26 torrs |
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Hemogolbin Saturation
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-at oxygen tension in arterial blood (100 mm Hg), hemoglobin is 95-98% saturated
-in venous circulation where oxygen tension is lower (~40 mm Hg), oxygen dissociates & oxygen is available to cells |
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Hill Coefficient (nH)
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-measure of cooperativity of O2 binding
-nH for hemoglobin is ~2.8 -nH for Mb is ~1.0 (means there is no cooperativity due to single polypeptide chain) |
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Increase in hydrogen ion concentration/decrease in pH (effect on hemoglobin O2 affinity)
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-decreases oxygen affinity of hemoglobin
-has no effect on myoglobin |
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Increase in CO2 tension (effect on hemoglobin O2 affinity)
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-shifts the dissociation curve to the right
-this means that when CO2 is present, hemoglobin has a lower affinity for O2 -about 13% of CO2 transported in blood back to the lungs as carbamate |
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Bohr Effect
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-linkage between O2, H+, & CO2
-about 0.5 H+ are taken up per O2 released -in high CO2, high H+ environment, O2 is released -hemoglobin is an important physiological buffer |
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Carbamino Compound
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~25% of the effect of CO2 on the oxygen dissociation curve is due to the formation of carboamino compounds
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Organic Phosphates in RBCs particularly 2,3bisphosphoglycerate (BPG) (effect on hemoglobin O2 affinity)
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-BPG increases at high altitudes
-reduces oxygen affinity of hemoglobin -BPG binds in the central cavity of deoxyhemoglobin & interacts with 3 positively charged groups on each beta chain -decreases oxygen affinity because it stabilizes the quaternary structure of deoxyhemoglobin by non-covalently cross-linking beta chains |
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Fetal Oxygen Transfer & Hemoglobin
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-Hemoglobin F (alpha2gamma2) binds BPG less strongly than Hemoglobin A & consequently has a higher affinity for oxygen
-this allows HbF to obtain oxygen at the expense of HbA on the other side of the placenta -gamma chain has a Ser substituted for His at position 143 --> losing positive charge = less interaction with negatively charged BPG |
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Increasing concentration of chloride ions (effect on hemoglobin O2 affinity)
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-shifts oxygen dissociation curve to the right
-chloride ions may further brace the deoxy-state by forming additional salt cross bridges |
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Increase in temperature (effect on hemoglobin O2 affinity)
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-decreases oxygen affinity & therefore increases p50
-temperature effects O2 binding of both hemoglobin & myoglobin |
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Oxygen Dissociation Effects (summary)
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-CO2, H+, 2,3-BPG, Cl-, & Temperature --> all decrease O2 affinity
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Allosteric Properties of Hemoglobin
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-arise from alpha-beta subunit interactions
-alpha chain by itself has a high oxygen affinity & dhyperbolic dissociation curve (also insensitive to pH, CO2, & BPG) -isolated beta chains for tetramers called hemoglobin H -separated chains lose cooperativity effects |
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BPG
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-net charge --> minus 4-5 charge at physiologic pH
-byproduct of glycolysis -one binding site on Hb tetramer (in center cavity) |
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[H+], CO2, & BPG
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-functionally competitive
-shift O2 dissociation curve to right |
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Oxy/Deoxy Quaternary Structure
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-most of the movement occurs at alpha1beta2(alpha2beta1) interfaces
-minimal movement at a1b1(a2b2) interfaces -a1b1 shifts 15% relative to a2b2 going from T state (deoxy) to R state (oxy) |
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Salt linkage constraints between chains of Deoxy Hb
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-these constraints are disrupted upon oxygenation
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In order for Hb to become oxygenated...
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-salt linkages must be broken & H+, CO2, and BPG bound to molecule are released
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When oxygen binds to iron atom...
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-iron moves into plane of Heme
-when there is no O2 bound, the atomic diameter of iron is too large for iron to sit flush with the porphyrin ring -the iron is displaced toward the proximal His --> moves back into heme plane when O2 is bound |
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OxyHb (R-state)
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-salt bridges between subunits are broken
-BPG expelled -tertiary & quaternary structure changed |
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Cooperation (salt bridges)
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-salt bridges must be broken to bind O2
-easier to break 2nd, 3rd, & 4th salt linkages once 1st one (and consecutive ones) are broken |
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Displacement of oxyhemoglobin dissociation curve in various clinical disorders
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-corrected to pH 7.4
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Dissociation curve shifted to the right
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1) Increase in red blood cell 2,3-BPG
-high altitude adaptation -pulmonary hypoxemia -cardiac right to left shunt -**severe anemia; decrease in RBC mass -congestive heart failure -decompensated hepatic cirrhosis -thyrotoxicosis -hyperphosphatemia (ATP also increased) 2) Functionally abnormal hemoglobin variants |
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Dissociation curve shifted to the left
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1) Decrease in red blood cell 2,3-BPG
-septic shock -severe acidosis -following transfusion of stored blood -hypophosphatemia -panhypopituitarism -neonatal respiratory distress syndrome 2) Functionally abnormal hemoglobin variants 3) Methemoglobinemia 4) Carbon Monoxide Intoxication |
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Severe Anemia; decrease in RBC mass
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-compensate for decreased RBCs by increasing [2,3-BPG]
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Carbomonoxyhemoglobin
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-hemoglobin combines ~200 times more strongly with CO than with oxygen
-forms a cherry-red compound called carboxyhemoglobin -Hb + 4 CO --> Hb(CO)4 -headaches & nausea occur is air contains ~0.02% CO -unconciousness & death can occur if air contains ~0.1% CO -smoking can block 20% of sites with CO -CO shows cooperativity as well -shifts curve to the left & O2 cannot be release to tissue |
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Hb & Mb reduce affinity for CO by...
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-by forcing a less preferred bent mode of binding
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Methemoglobin
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-form of hemoglobin where iron is in ferric (Fe+++) state
-cannot combine with & transport O2 -in normal individuals ~1.7% of hemoglobin is in the form of methemoglobin -certain drugs can increase the concentration of methemoglobin |
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Familial Methemoglobin
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-patients with a deficiency in the enzyme methemoglobin reductase
-if methemoglobin exceeds 10% of total Hb, patient will have clinically obvious cyanosis -if methemoglobin reaches 35%, patient will suffer headaches, weakness, & breathlessness |
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Structural Variants (resulting in essentailly normal amounts of an aberrant globin chain)
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-Single Base Substitution --> substitutes one AA for another (typically due to only one base change in a codon)
-Elongated Globin Chain Variants --> can be caused by base substitution in a termination codon, framshift mutation, or failure of cleavage of initiator Met residue -Shortened Globin Chains --> involve deletion of one or more intact codons -Non-homologous crossing over --> produce hybrid globin chains |
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Hemoglobin S
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-amino acid substitution on surface of molecule (altered exterior)
-mutant form of HbA in which Valine is substituted for glutamic acid at position 6 of beta chain -produces sickle cell anemia |
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Sickle Cell Anemia (epidemiology)
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1) American Blacks
-7-10% are heterozygous (HbAS; sickle cell trait) -0.4% are homozygous (HbSS; sickle cell anemia) 2) Protection from malaria --> infected AS cells --> knobs, stick to endothelial cells, clear 3) Treatment -hydroxyurea, 5-azacytidine (increase HbF) -bone marrow transplant -gene therapy |
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DeoxyHbS
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-insoluble --> sickle cells
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Altered Exterior
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-amino acid substitution on surface of molecule --> rarely causes clinical symtoms
-exception is HbS (sickle cell anemia) |
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Altered Active Site
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-defective subunit cannot bind oxygen due to structural change near heme that affects oxygen binding
-when either distal or proximal His is replaced by Tyr, heme is stabilized in ferric form & cannot bind oxygen -called HbM --> can only exist in heterozygotes since homozygotes would die -may be misdiagnosed as congenital heart disease in newborns due to cyanosis |
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Altered Secondary/Tertiary Structure
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-amino acid substituion can prevent polypeptide chain from assuming normal 3-D conformation
-resulting hemoglobin is usually unstable -can result in congenital Heinz body hemolytic anemia |
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Altered Quaternary Structure
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-mutations at subunit interfaces can lead to loss of allosteric properties
-often, these mutations increase oxygen affinity of the molecule |
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Thalassemia Syndromes
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-inherited disorder in which production of a single type of globin chain is either diminished or absent
-alpha & beta used to denote which chain is decreased or absent |
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Non-deletion form of B-Thalassemia
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-defects involve single base susbtitution or small deletions or insertions within or immediately upstream of the Beta Globin gene
-affects general aspects of gene functional transcription, RNA processing, & RNA translation |
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Deletion Forms of B-Thalassemia
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-deletions of different sizes involving B globin gene cluster
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A-Thalassemia due to deletion
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-deletion of one or more a-globin gene
-more complex & graded than B-thalassemia since there are 4 alpha gene loci |
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Non-deletion forms of A-Thalassemia
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-non-deletion forms caused by same type of mutation which cause non-deletion forms of B-Thalassemia (however, these types of mutations very rarely cause A-Thalassemia)
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Examples of A-Thalassemia
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-HbH Disease
-Hb Bart's Hydrops Fetalis |
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Pathophysiology of B-Thalassemia
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Review Chapter X (Notes 2) - Pg. 10
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Loss of Iron by Excretion
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-3.5 grams of Iron in Body
-0.1 mg/day lost in urin -0.1 mg/day by skin desquamation & sweat -0.3 mg/day by shedding of intestinal muscosa & biliary excretion -0.5 mg/day due to normal gastrointestinal bleeding |
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Additional Iron Needed For...
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-Rapid Growth
-Lactation -Pregnancy -Menstration |
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Dietary Iron
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-absorbed mainly by duodenum & jejunum
-heme iron --> found in meats, poultry, & fish -non-heme iron --> vegetables, fruit, nuts, grain, etc. |
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Transferrin
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-serum Fe+++ (hemin) transport protein
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Transferrin Receptor
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-glycoprotein that mediates uptake of transferrin
-used for cellular uptake/internalization or iron |
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Ferritin
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-cellular Fe+++ (hemin) storage protein
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Hemosiderin
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-denatured, insoluble ferritin
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Ferrochelatase
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-enzyme catalyzes insertion of ferrous iron (Fe++) into porphyrin to form heme
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Ferritin (properties)
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-24 subunits
-up to 23% iron by weight -4500 molecules of iron per molecule of ferritin |
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Regulation of Iron Absorption by Intestinal Mucosa
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Depends on:
1) Quantity of Iron in diet 2) Composition of diet 3) Behavior of Mucosa of Duodenum & Upper Jejunum |