Erythrocyte Biochemistry Flashcards
1
Q
What makes up fetal hemoglobin?
A
- 2 alpha
- 2 gamma
2
Q
What makes up adult hemoglobin type A?
A
- 2 alpha
- 2 beta
3
Q
What makes up adult hemoglobin type A2?
A
- 2 alpha
- 2 delta
- only makes up 3%
4
Q
Describe the structure of hemoglobin?
A
- tetramer
- one heme per subunit
- Has ferrous iron
- carries oxygen
- hydrophobic
5
Q
What happens to hemoglobin once oxygen binds?
A
- Before o2 binds iron is outside the plane of porphyrin
- Once it binds it moves into the plane of heme
- The change pulls down the proximal histiidine of Hb and changes interaction assoc with globin chain
6
Q
What will the ODC look like for myoglobin vs hemoglobin?
A
- Myoglobin is hyperbolic
- Hemoglobin is sigmoidal due to interactions between globin subunits (+ coorperativity, binding of one oxygen facilitates binding of next and so on)
7
Q
Where is the steepest part of ODC and what is the significance?
A
- It is between 40 torr which is pO2 at rest and 20 torr which is during exercise
- It indicates that Hb is very efficient during exercise with providing oxygen to tissues
8
Q
What does 2,3-BPG do to the ODC?
A
- reduces oxygen’s affinity so hemoglobin will give up oxygen easier to tissues
9
Q
How does the Bohr effect modify the ODC?
A
- CO2 and H are by products of actively respiring tissues, this enhances the oxygen delivery/release from hemoglobin
- pH of active tissue drops from 7.4 to 7.2
- This drops the binding affinity of Hb for O2
10
Q
Compare Fetal ODC and Mother ODC.
A
- Oxygen flows from mom to baby
- The gamma subunits have higher affinity than the beta for oxygen so the baby will not let it go as easy
11
Q
What mutation causes SCA?
A
- Glutamic acid changes to valine at position 6 in the beta chain
- This causes polymerization of Hb and sickle shaped RBC’s which impede circulation and cause hemolytic anemia
12
Q
How is iron regulated?
A
By modulating its absorption
13
Q
What is ferritin?
A
- Protien that will bind ferric iron to help store it
14
Q
What happens to ferrous iron when it enters an enterocyte?
A
- It gets oxidized to ferric iron by ferroxidase (Cerruloplasmin)
- It gets stored as ferritin and degraded to homosiderin
15
Q
How is non heme iron (Fe3) absorbed stored and transported?
A
- Plant products are difficult to absorb
- They get converted to Fe2 by ferric reductase (Dcytb) in the presence of vitamin C
- Fe2 will enter the enterocyte via divalent transporter 1 (DMT1)
- Gets converted to Fe3 by ferroxidase for storage or exported out via ferroportin
16
Q
What does ferroportin require to function?
A
- Needs hephaestin for function
- Ferroportin levels are regulated by hepcidin
17
Q
What protein binds Fe3 for transport to target tissues?
A
Transferrin
18
Q
How does uptake of transferrin occur?
A
- Via receptor mediated endocytosis with transferrin receptor
- It gets internalized with clathrin coated pits into endosomes and the low pH of endosomes releases transferrin from the receptor
- Iron gets taken up in mitochondria when the endosome docks and transfers it via DMT1 this is where heme is made
19
Q
What happens when hepcidin binds ferroportin?
A
- It causes internalization of ferroportin and its degradation in lysosomes
- It will bind when iron content is too high
20
Q
What regulates hepcidin?
A
- complex signaling path involving transferrin, receptor and a protein called human homeostatic iron reguolator protein
21
Q
When iron is high, hepcidin expression goes ___, ferroportin levels go ____, and iron absorption is now ____.
A
When iron is high, hepcidin expression goes up, ferroportin levels go down, and iron absorption is now decreased.
22
Q
When iron is low, hepcidin expression goes ___, ferroportin levels go ____, and iron absorption is now ____.
A
When iron is low, hepcidin expression goes up, ferroportin levels go up, and iron absorption is now high.
23
Q
Iron deficiency slilde 195
A
24
Q
what is hereditary hemochromatosis?
A
- Increased absorption of iron which accumulates in the heart, liver, and pancreas
- It causes liver cirrhosis, hepatocellulalr carinoma, diabetes, arthritis and heart failure
- Auto recessive mutation in HFE
25
What does a deficiency of folalte and B12 cause?
* megaloblastic macrocytic anemia due to decreased syntheiss of DNA in developing RBC bone marrow
* characterized by large erythrocytes
26
Describe folate metabolism.
* folate gets reduced to DHF by DHF reductase
* DHF gets reduced to THF via DHF reductase
* THF is the active form and important for synthesis of purines and pyrimidine thymine
* Serves a vital role in DNA synthesis
27
How long does the storage of folate last?
3-6 months in the liver
28
What is the primary active form of THF in the blood?
* Folic acid gets reduced to **N5-methyl-THF** once absorbed into the intestine
29
What is methotraxate?
* Binds to DHF reductase and inhibits it
* It is an antineoplastic agen that will inhibit DNA synthesis
30
What happens to THF if B12 isn't available?
* Folate trap occurs, as the B12 is a methyl acceptor and creastes Methyl-B12 and releases THF
31
How is B12 absorbed?
* Dietary B12 will bind to R-binder proteins
* Intrinsic factor made by parietal cells degrade R binder proteins in duodenum releasing B12
* IF carries B12 to ileium where it gets released in blood
* IF-Cobalamin is carried by Transcobalamin II in the blood and getss taken up by cells throug hreceptor mediated endocytosis
32
What is pernicious anemia?
* B12 deficiency can occur due to lack of IF, leads to a megaloblastic macrocytic anemia
33
What is the Schilling test?
* Used to figure out cause of Pernicious anemia
* Give radioactive Coalbamin and collect urine for 24 hrs looking for the radioactive B12
* if present it means normal absorption of B12 and the deficiency is in the diet
* If absent B12 isnt absorbed so pernicious anemia
* From pernicious anemia you give another dose of radioactive B12 PLUS IF
* Collect urine for 24 hours and if radioactive B12 is present its pernicious anemia due to lack of IF
34
What are the two key features of porphyrin rings?
* Four 5 membered rings with nitrogen
* Iron in ferrous state
* Oxidation to ferric state inactivates hemoglobin
35
Where does biosynthesis of heme occur?
* liver and erythroid cells of bone marrow
36
Where do phases one two and three of heme synthesis occur?
* Mitochondria
* Cytosol
* Mitochondria
* *Defects in any stage causes porphyrias*
37
What happens in phase one of heme synthesis?
* Within the mitochondria delta aminolevulinic acid is synthesized from glycine and succinyl coenzyme A
* It gets released from the Mitochondria
* *ALA Synthase*
38
What happens in phase two of heme synthesis?
* In the cytosol condensation of two delta ALAs form porphobilinogen (PB)
* Condensation of four PBs assemble the tetrapyrrole ring of coproporphyrinogen III
39
What happens in phase three of heme synthesis?
* Two oxidation reactions of coproporphyrinogen III to install side chain vinyll groups in protoporphyrinogen IX and make fully ocnjugated ring of protophorphyrin IX
* insertion of Fe2 with ferrochelatase
40
Succinyl CoA + GLycine=\_\_\_? This also requires what vitamin?
ALA is made and it requires B6 (PLP)
41
What does lead inhibit within the heme synthesis pathways?
* ALA dehydratase and ferrochelatase
* ALA is neurotoxic it contributes to the neuro sx of lead poisioning
* Heme production lowered
* **Causes microcytic and hypochromic anemia**
42
What are porphyrias?
* inherited metabolic disorders caused by defects in heme synthesis
* Purple pigment
* Can be acute hepatic or erythropoietic
* hepatic-neuro sx
* erythropoietic-photosensitivity
43
A defect in PBG deaminase in the liver will lead to \_\_\_\_.
* Acute intermittent porphyria
* It is auto dominant
* Deficiency leads to excessive production of ALA and PBG resulting in periodic attacks of ab pain and neuro dysfxn
* Hepatic
44
Uroporphyrinogen III synthase defect results in what condition?
* Congenital Erythropoietic porphyria
* Results in build up of Uroporphyrinogen I and its oxidation product of uroporphyrin I
* Produces red color in urine, teeth, and destroys RBC and causes skin photosensitivity
45
What is "Celebrity Porphyrias"?
* Variegate porphyria
* Includes intermittent episodes of abdomen pain, delirium, hallucinations, convulsions
46
what does heme oxygenase do?
* Clips heme and opens up the ring into a linear form to make biliverden
47
What does biliverdin reductase do?
* Adds two protons to biliverdin to make bilirubin
48
How do we get conjugated bilirubin from unconjugated and what does this do?
* add two glucuronate acid to bilirubin with **Bilirubin UDP glucuronyltransferase**
* Makes bilirubin more soluble
49
When bilirubin is released to blood what occurs after all the way to the end?
* It complexes with albumin and travels to liver where it gets conjugated with UDP glucuronyltransferase
* conjugated/direct bilirubin-diglucuronide goes to gall bladder
* galll bladder releases it to SI and it gets converted into bilirubin and then microbiota makes urobillinogen
* Urobillinogen either gets reabsorbed and converted in kidneys to urobilin OR not reabsorbed and converted into sterocobilin in LI and excreted as feces
50
What is jaundice?
* hyperbilirubinemia
* Elevated levels of BR in blood stream
* It is an imbalance btw production and excretion of bilirubin
51
What is a pre-hepatic jaundice?
* Increased production of unconjugated BR
* Excess hemolysis
* Internal hemorrhage can cause this as well as maternal fetal incompatibility
* Problem occurs before liver
52
What is intra hepatic jaundice?
* Impaired hepatic uptake conjugation or secretion of ocnjugated BR
* Can be causaed by general hepatic dysfxn
* Criggler-Najjar syndrome
* Gilbert syndrome
* Liver cirrhosis
* Viral hepatitis
53
What is post hepatic jaundice?
* AKA Cholestatic jaundice or cholestasis
* Problems with BR excretion caused by:
* cholangiocarcinoma
* gall stones
* Liver disease
* drugs
* obstruction to bile drainage
* Conjugated BR in the urine so dark urine
* Pale stool
54
Complete UDP-GT deficiency?
* Criggler Najjar syndrome
* Type one is complete absent of the gene resulting in severe hyperbilirubinemia causeing kernicturus
* Tx:
* blood transfusion
* phototherapy
* heme oxygenase inhibitors
* liver transplant
55
Mutation in UDP GT gene?
* Criggler Najar syndrome type II
* enzyme has about 10% activity
56
Gilbert syndrome?
* Common benign disorder resuts from reduced UDP GT
* 25% activity
* fasting stress or alcohol can increase BR
57
What is hepatitis?
* Inflammation of liver leading to dysfunction
* Caused by virus, alcoholic cirrhosis, or cancer
* Increased levels of unconjugated and conjugated BR in the blood
58
What is neonatal jaundice?
* Called Physiological jaundice
* Immature hepatic metabolic paths unable to conjugate and excrete bilirubin
* Deficiency of UDP GT enzyme bc not mature yet
* Breakdown of fetal hemoglobin as its replaced with adult
