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33 Cards in this Set
- Front
- Back
Which steps of protoporphyrin synthesis occur in the mitochondria?
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the initial step and the final three steps
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How many reactions are involved in heme synthesis?
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eight rxns
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Where does 85% of heme synthesis occur?
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In the erythropoietic marrow, the rest mostly happens in the liver
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What is the first step for heme synthesis? Where does it occur? What inhibits the enzyme in nonerythroid tissue?
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Succinyl CoA (from Kreb cycle) + glycine condense to form delta-ALA. Occurs in the mitochondria (Succinyl CoA formed in mito, and enzyme located there). Heme inhibits the enzyme delta-ALA synthetase.
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What is the second step of heme synthesis?
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Two delta-ALA condyse to form porphobilinogen (PBG). Enzyme is delta-ALA dehydratase. Occurs in the cytoplasm.
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What is the third step of heme synthesis?
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Four porphobilinogens (PBGs) linked by porphobilinogen deaminase to form linear hydroxymethylbilane. cytoplasmic.
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What is the fourth step of heme synthesis?
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linear tetrapurole (hydroxymethylbilane) cyclizes into uroporphyrinogen III. cytoplasmic.
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After the fourth step of heme synthesis, what are the last several steps of heme synthesis?
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alter the functional groups of the porphyrin skeleton. last step is incorporation of ferrous iron in to the protoporphyrin to form heme.
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What is the last compound that is formed in the cytoplasm for heme synthesis?
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coproporphyrinogen III. This enters the mitochondria for the last three steps.
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What is the last enzyme of heme synthesis and where is it located?
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ferrochelatase (heme synthetase). reaction occurs in the mitochondria.
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When monoblasts contain low levels of heme due to low levels of iron what is the level of protoporphyrin?
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Because heme is low, the neg. feedback of delta-ALA synthetase is not active. This leads to a high level of protoporphyrin. This is caused by iron deficient anemia.
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What delivers iron to erythrocytes? What oxidation state is the iron in? How many irons are transfered? What happens to the compound after iron delivery?
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Transferrin transports two irons in the ferric state (3+). After delivery the transferrin is recycled.
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How is heme synthesis regulated in nonerythroid tissues?
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Heme suppresses ALA-S1 (synthetase). This is the rate limiting step. ALA-S1 is also known as the house keeping isoform of ALA-S.
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How is heme synthesis regulated in erythroid tissues? What else does it have to help regulate synthesis?
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ALA-S2 has iron response element (IRE). Heme inhibits the cellular acquisition of iron from transferrin. Proteins bind to the IRE based on iron availability thus controlling the ALA-S2 translation and ALA formation.
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What are the porphoryias?
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Metabolic disease characterized by (usually genetic) deficiencies of specific enzymes needed for heme synthesis.
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How are the porphyrias divided?
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hepatic and erythropoietic
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Explain the mechanism of congenital erythropoietic porphyria. Which enzyme is missing, where is it, what compound builds up? What happens to RBCs, what is the clinical manifestations? What is therapy?
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Missing uroporphyrinogen III cosynthetase (step 4 of heme synthesis). It is erythropoietic, and uroporphyrinogen I builds up. RBC prematurely destroyed (anemic) and urine is red (from uroporphyrin I). light sensitive, teeth fluorescent. treat with hematin (form of heme) or blood transfusions.
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Explain the mechanism of acute intermitent porphyria. Which enzyme is depressed? What is the effects of this depression? What are the clinical manifestations? What is the treatment?
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In the liver, the porphobilinogen deaminase (step 3) is depressed. This causes a compensatory increase in delta-ALA synthetase. There is an increase in delta-ALA synthetase and porphilinogen (seen in liver and urine). Clinically seen as intermittent abdominal pain and neurological disturbances. Treat with hematin (form of heme).
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What are the two tasks of hemoglobin?
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Delivery of O2 from lungs to tissue. Removal of CO2 from tissue to lungs.
NOTE: it also acts as buffer for H2CO3 |
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What is the P50 for hemoglobin?
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The partial pressure of oxygen where there is 50% saturation of the heme with O2.
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When the iron of heme is oxidized to 3+, hemoglobin is called what?
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methemoglobin.
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What fills the six coordination sites of iron in oxy hemoglobin?
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four nitrogens from the porphyrin ring, a nitrogen from the proximal histidine, and O2.
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How many chains and hemes are in hemoglobin? What is the shape of the binding curve? What effect of this curve?
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Four chains each with a heme which enables a sigmoid binding curve. This allows for better release of O2 at the tissue than Mb.
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What are thre modifying agents on hemoglobins sigmoid curve?
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Bohr effect, CO2 effect, 2,3-diphosphoglyceric acid (DPG).
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Many forms of hemoglobin exist. How are these Hb ID?
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ID with electrophoresis.
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What is HbA1c
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It is the glucosylated form of of HbA. Glucose is added to the N-terminal of the beta chains. In diabetics this form can be 6-17% (normal is up to 3%).
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What are the three normal hemoglobins?
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HbA (alpha2beta2), HbA2 (alpha2delta2), HbF fetal (alpha2gamma2)
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What is the structure of HbS?
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Sickle cell hemoglobin has a chain at the sixth aa of the beta chain from Glu to Val. alpha2betaS2
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What is Hb Barts and where is it seen?
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HbBart is gamma4. It is seen in alpha thalassemia.
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What is the progression of hemoglobin in fetal development?
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Hb Grower present in embryo (alpha2epsilon2), HbF (alpha2gamma2), in adults this changes to mostly HbA (alpha2beta2)
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What is the difference in hemoglobin between the oxy and deoxy form?
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In the deoxy form the porphyrin is bowed and the structure is the taught form. In the oxy form the O2 pulls the ring into a linear structure and pulls the proximal histadine creating a more relaxed structure. As a result the subsequent binding of O2 is easier.
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What is the Bohr effect?
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O2 affinity of Hb is pH dependent. There is a release of O2 at the tissues which have a lower pH. Binding of protons facilitates the release of O2. This helps O2 be delivered to where it is needed.
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How does 2,3-diphosphoglyceric acid (DPG) change the oxygen affinity curve of hemoglobin?
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DPG right shifts the oxygen curve. DPG binds to the deoxy form of Hb and binds to HbF. This allows fetal blood to have a higher O2 affinity.
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