NBME - 6/9 - RBC Metabolism and Heme Synthesis Flashcards
What do Basophils do
Allergic reactions, degranulation releases histamine, heparin, leukotrienes, etc.
Monocytes?
Circulating precursors of tissue macrophages
Most common granulocyte in the body?
Neutrophils
Life span for RBCs, WBCs, and platelets
RBCs = 120 days
Platelets = 8-10 days
Neutrophils/WBCs = 6 hours
Discuss the reaction involving Basophils for something like a Bee sting
Bee sting, venom into blood, we make an antibody which binds to the basophils and waits for round two. Bee sting again causes antigen to bind to FC portion of the basophil antibody, causing agglutination and activativation, leading to the release of histamine to vasodilate and increase fluid excretions, which presents as constricted airways and struggle to breathe
Function of Erythropoietin. When is it released?
Stimulates erythrocyte maturation. Released from the kidney at low O2 conditions and acts on cytokine receptors of erythroid progenitor cells, stimulating their proliferation and maturation.
Problem with Kidney failure for the blood
Kidney failure means no EPO, so there is nothing to mature the RBCs, causing an anemia
Erythroid progenitor cells (CFU-E) undergoes how many rounds of division in the bone marrow? When does Hemoglobin synthesis begin?
4 divisions. Hemoglobin synthesis begins in cells that have undergone the first division
True or False: When the new RBC is released from the bone marrow, there is no nuclear material in it
False. We lose the nucleus prior, but when this cell gets released into the blood from the bone marrow, it still has ribosomal material and RNA. This cell, called a reticulocyte, will mature in the blood quickly and turn into a normal RBC. Important note: Heavy hematopoiesis means lots of cells being churned out quickly. The reticulocytes will be released earlier than usual, and will have their ribosomes and RNA material a little longer than usual. These high reticulocyte counts are indicative of high hematopoietic activity.
Oxidative stress in the RBC is very high. How do we manipulate glycolysis in the RBC to handle this stress? Read this long Flash card, its wordy in order to make sense. Not really that bad.
It’s all about playing hot potato with the oxidation. We start with some oxidizing dangerous agent in the blood. Gutathione peroxidase reduces that molecule and in the process has to pass on the oxidative stress to something else, in this case, reduced glutathione, which generates oxidized glutathione.
But oxidized glutathione doesn’t like this, it wants to be reduced again. It passes that nonsense onto NADPH with help from glutathione reductase, turning NADPH into NADP+ (so now oxidized glutathione is reduced glutathione, and NADPH is pissed because it’s oxidized to NADP+).
This is where glycolysis comes in to play with the Hexose monophosphate shunt, which takes the Glucose-6-P we made from glucose and gives it the oxidative stress, thus turning our angry NADP+ to NADPH. It does this with G6PDH.
Our angry oxidized glucose-6-P gets recycled to Fructose 6-P to continue on with Glycolysis after going through the HMP shunt.
Summary:
Most common enzyme deficiency in humans
G6PDH deficiency
Another important shunt used by RBS is the one that reduces Hemoglobin back to Fe2+. Recall that Met-Hgb is the inactive form, the oxidized form. Sometimes in the RBC, the good Fe2+ hemoglobin gets turned back into Fe3+ Met-Hgb. Outline the mechanism for reducing Met-Hgb back to what it is supposed to be
Fe3+ Hgb gets reduced to Fe2+ by Reduced Cytochrome b5, which then turns to Oxidized cytochrome b5.
NADH restores the oxidized cytochrome b5 back to reduced cytochrome b5 by taking on the stress and turning in to NAD+.
Glycolysis restores NAD+ back to NADH.
What causes methemoglobinemia?
An issue with Cytochrome b5 reductase, which is needed to allow NADH to reduce the now oxidized cytochrome b5 back to its reduced cytochome b5 form. Because we can’t do that, the shunt shuts down and Fe3+ stays oxidized as met-hgb in the blood. So we can’t carry oxygen!
Outline the Rapoport Luebering shunt and why it is important.
We use this shunt to generate 2,3 BPG. An increase in 2,3-BPG at low O2 conditions adjusts our O2 saturation curve for better performance (right shift of the curve) Mutase turns 1,3 BPG in the glycolysis cycle to 2,3 BPG, which can be put back into the glycolysis cycle by phosphatase as the next glycolysis step, 3 phosphoglycerate.
What does a rightward shift in the Hgb curve really mean? It’s important to understand this
A rightward shift indicates that the hemoglobin under study has a DECREASED AFFINITY for oxygen. This makes it more difficult for hemoglobin to bind to oxygen (requiring a higher partial pressure of oxygen to achieve the same oxygen saturation), but it makes it easier for the hemoglobin to release oxygen bound to it, so we can unload more O2 to tissues. The effect of this rightward shift of the curve INCREASES PARTIAL PRESSURE of oxygen in the tissues when it is most needed, such as during exercise, or hemorrhagic shock
Relate BPG to fetal hemoglobin
In Fetal hemoglobin, a histidine is replaced by serine, not as many charges for BPG to bind to, so it doesn’t really have much of an effect. The fascinating thing, is that 2,3 BPG mutase exists at the fetal-maternal junction to allow the maternal blood to give up its O2 more easily to the fetal hemoglobin.
Pyruvate kinase deficiency leads to what and why
The 2nd to last step of glycolysis is turning PEP to Pyruvate, turning ADP to ATP in the process via a pyruvate kinase. Without this pyruvate kinase, the cell doesn’t generate ATP, and low energy RBCs means hemolytic anemia.
The erythrocyte has a cytoskeleton, which becomes affected in diseases like Hereditary Spherocytosis, an autosomal dominant disorder of RBCs. Discuss the major protein involved in the cytoskeleton of RBCs and what it attaches to
The major protein, spectrin, is linked to the plasma membrane through one of two ways:
- Interaction with Ankyrin and band 3 (chloride-bicarbonate antiporter) or
- With actin, band 4.1, and glycophorin
These combine to make a mesh-like framework
Discuss formation of the heme precursor Porphyrinogen
Basic building block is a pyrrole, a 5 carbon ring with a Nitrogen between two of the carbons. 4 Parroles come together putting their Nitrogens towards a center area and linking together with 1 carbon in between each parrole, making a porphyrinogen, which is colorless because it only has unconjugated double bonds, not conjugated.
Coming off the outside carbons of this big tetrapyrrole (Porphyrinogen) are Acetates, Methyls, Vinyls, and propionates. How do we distinguish different types of porphyrinogens?
Based on these outside molecules.
Uro-porphyrinogen = A’s and P’s
Copro-porphyrinogen = M’s and P’s
Final stage: Proto-porphyrinogen = M’s, V’s, and P’s
Porphyrinogens become porphyrin how?
Spontaneous oxidation! Conjugated double bonds, and now we are red because we are conjugated! So the red comes from porphyrin, not the iron, interesting.
How do we make heme?
Need to take our coolest porphyrinogen, Proto-porphyrinogen (it has all three extensions so we like it more), mature it spontaneously to protoporphyrin (protoporphyrin IX is a particular isotype we care more about for whatever reason), and then shove an Fe 2+in the middle to make Heme.
If there is no globin around when we make Heme, like when we’ve already made a ton of hemoglobin, what happens to the heme?
It turns to hematin/Hemin, an Fe 3+ form of heme that inhibits further creation of heme.
How does Hemin/Hematin stop synthesis of new Heme? Discuss where it inserts into the cycle to stop things.
We get the carbons to make heme from succinyl CoA and glycine coming together with ALAS to make ALA. This begins the long process. Hematin directly inhibits ALAS and also indirectly inhibits ALAS by inhibiting its transport into the mitochondrion.
