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MCM-COM 2018 > Erythrocyte Biochemistry > Flashcards

Erythrocyte Biochemistry Flashcards

1
Q

Describe the steps of erythropoiesis (making of RBC’s)

A

Stem cell (hemocytoblast) —> committed cell (proerthroblast) —>phase 1. Ribosome synthesis (early erythroblast) —> phase 2. Hemoglobin accumulation (late erythroblast) —> (normoblast) —> phase 3. Ejection of nucleus and organelles (reticulocytes)—> Erythrocyte (RBC)

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2
Q

T/F

Majority of hemoglobin synthesis is before the release of the nuclear from the cell in erythropoiesis

A

True

*small amounts are made in reticulocytes

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3
Q

Describe the adult hemoglobin structure

A
  • tetrameric protein
    • 2 alpha-globin chains
    • 2 beta-globin chains
  • one heme
    • holds iron Fe2+ (ferrous)
    • holds the oxygen
    • is hydrophobic
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4
Q

What are the embryonic hemoglobin cells called? And when are they destroyed?

A

Hgb Gower 1
Hgb Gower 2
Hgb Portland

*by 8 weeks gestation

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5
Q

What is the name for fetal hemoglobin? When does it peak?

A

Hgb F (A2, Y2)

-peaks right before birth

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6
Q

What is the name for adult hemoglobin?

A 
Hgb A (A2, B2) —97 %
Hgb A2 (A2, S2) — 3%

*after birth gamma (Y) Hgb decreases and alpha (A) increases

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7
Q

What genes are associated with hemoglobin (adult, embryonic, and fetal)

A

16 and 11

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8
Q

Current research for sickle cell treatment is trying to induce expression of ______. Why?

A

HbF (fetal hemoglobin)

  • upregulated HbF because it doesn’t have Beta component. The mutation for sickle cell is on the B-globin unit, therefore without it there is no sickle cell disease
  • using hydroxyurea to induce HbF and address inflammation

*BUT urea is toxic agent

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9
Q

Where is the missense mutation of glu—>Val found in sickle cell anemia

A

HbS - amino acid #6 in B-globin

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10
Q

What are the traits associated with proximal histidine

A
  • F8
  • bound to heme
  • Beta chain of hemoglobin
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11
Q

What are the traits of distal histidine

A
  • E7
  • stabilizes O2 bound to heme through hydrogen bonding
  • beta-chain of hemoglobin

*O2 binds to the iron between the heme and distal histidine

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12
Q

How does Oxygen binding cause a conformational change in hemoglobin

A
  • oxygen binding changes the position of iron in the plane of the heme
  • the change pulls down the proximal F8 histidine and changes interaction with associated globin chain

(Slight angle) deoxymyoglobin —-(O2 binding —-> (more straight) oxymyoglobin

*positive cooperatively

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13
Q

What is the concentration of O2 when hemoglobin is 50% saturated

A

26 Torr

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14
Q

Why is the oxygen dissociation curve sigmoid all for hemoglobin and hyperbolic for myoglobin

A

-the sigmoidal shape indicates that distinct oxygen binding sites are present in each hemoglobin molecule

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15
Q

T/F

Hemoglobin bind to oxygen is reversible

A

True

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16
Q

T/F hemoglobin switches between 2 affinity states: low and high

A

True

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17
Q

Explain positive cooperatively between hemoglobin and oxygen that makes hemoglobin more superior to myoglobin

A
  • the binding of one oxygen to hemoglobin facilitate the binding of oxygen to another heme (makes it easier and easier)
  • the conformational change of one globin subunit induces a conformational change in another subunit
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18
Q

The oxygen dissociation curve: modulation by pH illustrates what ?

A

The Bohr effect

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19
Q

Is the pH of actively respiring tissues higher or lower

A

Lower

7.4 –> 7.2

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20
Q

How is the binding affinity of hemoglobin for oxygen affected when pH decreases

A

The binding affinity of Hb for O2 decreases as pH decreases

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21
Q

Which histidine residue picks up H+ ions from tissue

A

His 146

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22
Q

Cooperativity enhances oxygen delivery by hemoglobin. Hemoglobin is able to deliver more O2 to actively metabolizing tissues as compared to ______ or _____ even if they have optimal O2 affinity

A

Myoglobin

Or non cooperative protein

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23
Q

What is responsible for reducing oxygen affinity so Hb gives up more O2 to the tissues

A

2,3 BPG

  • signals Hb to let go of O2 so more can be delivered to tissues
  • this is the reason why pure Hb binds O2 more tightly vs Hb in RBC’s (bc of 2, 3 BPG presence in RBC)
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24
Q

T/F

Fetuses need Hb that has higher affinity for O2 vs mothers Hb

A

True

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25
Q

What does not bind well to 2,3 BPG and therefore has a higher affinity for O2

A

HbF (fetal Hb)

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26
Q

What protein carries iron in the blood

A

Transferrin

*provides iron to bone marrow for RBC formation

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27
Q

T/F

Macrophages will digest RBC’s and release the iron to go back into the iron cycle

A

True

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28
Q

Where is iron mainly found in humans

A

67% in hemoglobin

  • 27% storage in ferritin and hemosiderin
  • 5%myoglobin
  • 1% Fe-proteins
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29
Q

What are the two storage forms of iron

A

Ferritin - water soluble

Hemosiderin - water insoluble

30
Q

What is Fe2+ iron form

A

Ferrous

31
Q

What is Fe3+ iron form

A

Ferric

32
Q

Heme iron starts is also known as

A 
Ferrous iron (Fe2+)
 “Free iron”
33
Q

Non-heme iron is also known as

A

Fe3+ (Ferric)

34
Q

What are the other names of ferroxidase? And what does feroxidase do? And what cofactor does it need?

A

Cerruloplasmin or hephaestin

  • converts Fe2+ to Fe3+
  • converts ferrous to ferric

*need copper

35
Q

What is another name for ferric reductase? What does it do? And what coenzyme does it need?

A

Duodenal cytochrome B

  • coverts Fe3+ to Fe2+
  • converts ferric to ferrous

*ned vitamin C

36
Q

What does DMT1 do?

A
  • places a role in non-heme iron absorption

- takes up Ferrous into the enterocyte

37
Q

What does ferroportin do? What activates and inhibits it?

A

Moves iron out of the cell into the blood

  • activated by low dietary iron
  • inhibited by hepcidin and high dietary iron
38
Q

What form of iron does transferrin carry to the bone marrow through the blood

A

Ferric (Fe3+)

39
Q

Iron content in the body is regulated by modulating absorption. What peptide hormone is responsible for this/

A

Hepcidin

40
Q

How does transferrin uptake occur

A

By receptor-mediated endocytosis via transferrin receptor (TfR)

  • internalized via clathrin coated pits (endosomes)
  • DMT1 transports iron out of the endosomes
41
Q

Why is transferrin uptake very efficient in mitochondria

A
  • heme is made in the mitochondria
  • the endosomes docks on the mitochondria and transfers iron directly to the mitochondria without the need of a transport protein (no TfR)
42
Q

What type of anemia is caused by iron deficiency

A

Hypochromic microcytic anemia

*treat with iron supplements

43
Q

Mutated HFE gene results in no hepcidin to slow iron absorption therfore causing toxic levels of iron in the body. What disease is this related to?

A

Hereditary hemochromatosis

*organ dysfunction due to iron overload

  • normal iron stores in body = 3-5g
  • hereditary hemochromatosis = 15g
44
Q

What does hepcidin affect to cause a reduction in iron absorption?

A
  • binds to ferroportin
  • causes internalization of ferroportin
  • causes ferroportin destruction by proteolysis
45
Q

As hepcidin levels increase, ferroportin transporter levels ______

A

Decrease

46
Q

When iron is high:

Hepcidin levels are _____

Ferroportin levels are _____

And

Iron absorption is ______

A

Up

Down

Low

47
Q

When iron is low:

Hepcidin levels are ____

Ferroportin levels are _____

Iron absorption is _____

A

Low

Up

High

48
Q

How is hepcidin expression regulated

A

By transferrin receptors (Tfr1 and Tfr2) in hepatocytes (liver)

*if lots of transferrin in the blood, the Hfe complex moves from Tfr1 to Tfr2 which sends signals to increase hepcidin expression

49
Q

Mutated Hfe means it can not bind to TfR2, and then there is no hepcidin formation. This leads to no control of ferroportin and iron toxicity. What disease is this related too

A

Hemochromatosis

50
Q

Anemia of chronic disease can be caused by _____

A

Hepcidin over expression and blocking of adequate iron absorption.

Cause microcytic hypochromic anemia

51
Q

RBC formation is dependent on what vitamins

A

B12 (cobalamin)

And

Folate (folic acid)

*and continual DNA synthesis is needed

52
Q

Vitamin B12 and folate can cause what type of anemia

A

Megaloblastic Macrocytic anemia
[MCV > 100]

*from dismissed synthesis of DNA in developing RBC in bone marrow

53
Q

What is the normal MCV for a RBC

A

80-100

Macrocytic = >100

54
Q

T/F

Megaloblastic macrocytic anemic RBC’s have the same hemoglobin content as normal RBC

A

True. Its not hypochromic so it not hemoglobin def

55
Q

A blood smear of megaloblastic macrocytic anemia will show enlarged RBC and ____

A

Multi-lobed neutrophils

56
Q

How many parts are involved in the structure of folate

A

3

57
Q

What is the active form of folate? What important role does it play?

A

THF (tetrahydrofolate)

  • important role in DNA synthesis
  • serves as a 1 carbon donor
58
Q

What is the enzyme that converts folate to dihydrofolate (dietary folate) to tetrahydrofolate

A

Dihydrofolate reductase

Uses NADPH

59
Q

THF grabs methyl (1 Carbon) groups using 2 nitrogen’s at what position on the molecule

A

@ 5 and 10

60
Q

How does methyl get trapped in the folic acid pathway

A

THF —> methylene (added to nucleotide formation) —> methyl

Methyl —> THF *but needs B12

B12 DEFCIENCY MAKES IT TRAPPED

61
Q

What folate component give carbons for nucleotides

A

Methylene

  • carbon of methylene-THF is transferred to dUMP to form dTMP for DNA synthesis.
  • DHF is regenerated and reduced by dihydrofolate reductase to THF to restart the cycle

*THEREFOR FOLIC ACID DEF = LESS DNA = MEGALOBLASTIC ANEMIA

62
Q

The main carbon transfer in folate metabolism occurs when the carbon side chain of ______ is transferred to THF to form methylene-THF

A

Serine

63
Q

Where is folic acid absorbed

A

Jejunum of the small intestine

DHF—> THF in blood

64
Q

What are the liver stores of folate and how long fo they last

A

5-10mg

3-6 months

65
Q

What does B12 do to methyl-THF that allows it to donate a methylene group to dUMP to make dTMP for DNA synthesis

A

Demethylates it

*makes methyl-cobalamin to release THF back into cycle

66
Q

What does cobalamin do with it becomes methylated

A

Transfers the methyl group to homocysteine to create methionine using methionine synthase

*remember B12 MAKES METHIONINE

67
Q

What is needed for B12 absorption

A

Dietary B12 bind to R-binder proteins

Proteases degrade R-binder in duodenum to release B12

Intrinsic factor (from parietal cells) carries B12 to ileum where it can be absorbed by receptor mediated endocytosis

68
Q

What carried B12 (cobalamin) thorough the blood

A

Transcobalmin

69
Q

What causes pernicious anemia?

A

Lack of IF can cause B12 Deficiency which causes pernicious anemia

  • megaloblastic macrocytic anemia
  • usually autoimmune related (decreases gastric mucosa)
70
Q

Which test allows s to see the cause of anemia

A

Schilling Test

71
Q

Explain how the schilling test part 1 works

A
  1. A little bit of Radioactive labels B12 is dosed with a lot of unlabeled B12
    (Unlabeled B12 saturate all B12 receptors to prevent radioactive binding, if it absorbed from the GI it will pass into urine)
  2. Urine is collected for 24 hours
  3. Look for presence of B12
    *if B12 present then normal absorption of B12 and diet deficiency is the answer
    *if B12 is absent then B12 was not absorbed and pernicious anemia (lack of IF) is considered and need a part 2 test
72
Q

Describe how schilling test part 2 works

A

*already identified pernicious anemia from lack of radioactive B12 in the urine in part 1

  1. High dose of unlabeled B12 and low dose of labeled B12 AND ADD INTRINSIC FACTOR
  2. Urine collected for 24 hours
  3. If radioactive B12 is present in urine then pernicious anemia is due to lack of IF

MCM-COM 2018 (14 decks)

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