Biochemistry-Erythrocytes & Heme Flashcards
Avg concentration of RBCs in blood
5,000,000 cells per mm^3
You cut your finger and it gets infected. How long does the 1st neutrophil live that gets to the infected tissue?
6 hours in the blood, dies off after being in the tissue for only 1 or 2 hours
What cells in the blood are involved in anaphylactic shock?
Basophils
Where does erythropoiesis start?
The pluripotent stem cell divides in its nitch -> differentiates into a multipotent cell -> committed stem cell
What role do the juxtaglomerular cells play in erythropoiesis?
They sense oxygen and release the cytokine EPO. EPO promotes formation of BFU-E -> CFU-E -> Pronormoblast -> Normoblast -> Reticulocyte -> Erythrocyte
What drug is commonly given with EPO for people with anemia?
Fe2+
How does the erythrocyte protect itself from oxidative damage?
Glucose enters erythrocyte -> Hexokinase makes Glc6P -> Glc6P dehydrogenase makes NADPH -> NADPH reduces oxidized glutathione peroxidase -> Reduced glutathione peroxidase reduces oxidizing agents to alcohols.
Why is G6PDH the most common RBC enzyme mutation in the world?
Natural selection by malaria. G6PDH deficiency results in early erythrocyte death and decreased time for malaria parasites to replicate inside our blood.
What mutation of an erythrocyte enzyme could result in an overall decrease in the ability of hemoglobin to bind oxygen?
Cytochrome b5 reductase. It takes the NADH -> reduces cut b5 -> reduced cut b5 reduces Fe3+ methemoglbin to Fe2+ hemoglobin. If Cyt b5 reductase were mutated you would see methemoglobinemia.
How do erythrocytes adjust at high altitudes to maintain blood oxygen levels?
2,3-BPG made in the Rapoport-Luebering shunt. 2,3-BPG binds to the deoxygenated form of Hgb, making Hgb unload its oxygen more readily to keep tissues perfused.
What turns on 2,3-BPG synthesis so you can sustain blood oxygen at high altitudes?
Higher blood pH, from respiratory alkalosis, increases the activity of the mutase that converts 1,3-BPG -> 2,3-BPG
How does 2,3-BPG help the fetus get more oxygen?
The mother has increased levels of 2,3-BPG at the placenta to increase O2 unloading for the fetus.
How does pyruvate kinase deficiency cause anemia?
There is decreased ATP production, which decreases the RBC’s ability to pump ions out and the cell gets damaged.
Why is the shape of the RBC important for O2 exchange?
The biconcave disc has more surface area than a sphere does
What allows the lysed RBC (ghost cell) to maintain the biconcave disc shape?
Spectrin. It is a long fibrous molecule. It forms a fibrous network beneath the plasma membrane and is linked to the plasma membrane’s glycophorins by the proteins ankyrin, band and actin.
What type of anemia develops from defects in the RBC membrane proteins?
Typically autosomal dominant hereditary spherocytosis. The cell loses its biconcave disc shape and can no longer squeeze through small spaces like it needs to. This is why you see the macrophage-made bite cells after they come out of the spleen.
What makes up heme?
4 pyrroles cyclize and form a porphyrinogen. Porphyrinogens with acetates and proprionates around the edge are called uroporphyrinogens. Uroporphyrinogen III is oxidized so that it is conjugated to form protoporphyrin IX. Fe2+ is added inside and you get heme.
How does B6 deficiency cause anemia?
Delta-ALA synthase needs PLP, which needs B6 to function. Failure to convert succinyl CoA and glycine to delta-Aminolevulinic acid results in an inability to make heme. If you can’t make heme, you will have microcytic anemia.
What molecule does feedback inhibition in the synthesis of heme in the liver?
Hemin. It inhibits ALAS (delta-ALA synthase) transcription, translation and transport to the mitochondria. When hemin falls, ALAS activity is increased.
How does lead toxicity cause anemia?
Pb2+ inactivates ALAD (delta-ALA dehydratase). This prevents the 2 delta-ALAs from combining to form a pyrrole. Pb2+ also inhibits insertion of Fe2+ into heme by inhibiting ferrochelatase.
What type of light-sensitive porphyria results in excess uroporphyrinogen I that gets converted to different porphyrinogens that get excreted in the urine and feces?
Congenital erythropoietic porphyria = deficiency of URO III cosynthase. This enzyme is responsible for forming the uroporphyrinogen III isomer. The type I isomer goes on to form a porphyrin and you get a terribly light sensitive porphyria.
A patient comes to the ED agitated and very confused. Physical exam reveals tachycardia. He has a history of similar attacks in the past as well do people on his father’s side. Labs reveal increased levels of urinary ALA and PBG and microcytic anemia. What is causing his symptoms?
Acute intermittent porphyria. This is a defect in the enzyme PBG deaminase (UROS) that links the 4 pyrroles together.
A 22 year old woman comes to the ED after spending an hour smoking in the sun with blistering lesions. Labs reveal excess uroporphyrin III excreted in the urine and microcytic anemia. What is causing her symptoms?
Porphyria cutanea tarda. This is a result of decreased uroporphyrinogen decarboxylase. Excess uroporphyrinogen III spontaneously converts to a porphyrin, which absorbs light and causes tissue damage. Note that symptoms don’t present until adulthood because adulthood = induction of P450 enzymes, which requires more heme.
How does the cell know when to synthesize more globin to match the large amount of heme produced?
Excess heme is converted to hemin. Hemin inhibits the kinase that inactivates eIF2. eIF2 is activated and globin synthesis is initiated to produce more globin.
How does puberty affect heme synthesis? How does this relate to giving phenobarbital to a patient with a light-sensitive porphyria?
During puberty you need more steroid hormones produced. This requires induction of CYP450 and lots of heme is used. This decreases the amount of hemin present, increases synthesis of ALA synthase and turns on the heme synthesis pathway. Drug detoxification does the same thing to CYP450, turns on heme synthesis and will increase the amount of porphyrins that can damage the patient when exposed to the sun.
