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Flashcards in Erythrocyte Biochemistry Deck (115)
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1
Q

Structure of Hb

A

Hb is a tetramer, made up of [2 alpha globulin subunits] and [2 beta globulin subunits]

2
Q

Heme

A

Heme is a HYDROPHOBIC prosthetic group that binds O2. There is 1 heme/subunit in Hb. So 4 hemes total.

Heme is made up of protophoryin IX and Fe2+.

3
Q

For O2 to bind to heme, Fe must be in the ___ state

A

2+

4
Q

Fe2+ is called

A

ferrous

5
Q

What is erythropoiesis?

A

Erythropoiesis is the creation of RBC

6
Q

What is the process of erythropoiesis

A
  1. Stem cell (hemocytoblast)
  2. Committed cell (proerythroblast)
  3. It then undergoes a developmental pathway where
    A. ribosomes are made
    B. Hb is made
    C. nucleus and a majority of organelles are ejected
    because RBC do not have organelles and have already
    made their Hb
  4. Erythrocyte
7
Q

In the formation of a RBC, a majority of the ____ is made before the nucleus is ejected

A

Hb

8
Q

Embroyonic Hb

A
  1. Hb Gower 1
  2. Hb Gower 2
  3. Hb Portland

By 8 weeks of gestation, they’re destroyed

9
Q

Fetal Hb

A
  1. Hb F (alpha2gamma2)
10
Q

Adult Hb

A
  1. Hb A (alpha2beta2) –> 97%

2. Hb A2 (alpha2delta2)–> 3%

11
Q

What chromosome are responsible for the creation of Hb?

A

Chromosome 16

Chromosome 11

12
Q

Sickle cell anemia is caused by a change in?

A

In HbS. the AA at position #6 of B-globulin chain changes from Glu–> Val

13
Q

What are researchers trying to do to tx Sickle Cell Anemia?

A

Researchers are trying to induce the expression of HbF using hydroxyurea.

However, it is chemically.

14
Q

Heme is stabilized by _____

A

Histadine

15
Q

There are 2 histadines

A
  1. Histidine F8

2. Histidine E7

16
Q

Histidine F8

A

Histidine F8 is the proximal histidine.

It connects the heme to the Hb.

17
Q

Histidine E7

A

Histidine E7 is the distal histidine.

O2 binds to the Fe that is located between heme and Histidine E7.

18
Q

Myoglobin has a _____ curve

A

hyperbolic

19
Q

Hemoglobin has a ____ curve

A

sigmoidal because it participates in positive cooperativity

20
Q

hb switches between ____ and _____ affinity

A

high and low

21
Q

Is the binding of 02 reversible?

A

Yeth

22
Q

positive cooperativity in hb

A

the binding of 1 O2 molecule will facilitate the binding of another O2 molecule.

A conformational change in 1 globin subunit will induce a conformational change in another subunit. How does this happen? When O2 binds to Fe2+, it causes a 0.4A change, pulling down the proximal F8 histidine, which changes the interaction with the associated globin chain.

23
Q

What happens when O2 binds to Fe2?

A

When O2 binds to Fe2,

It causes a 0.4A change, pulling down the proximal His F8. this changes the interaction with the associated globins to that O2 can better bind. POSITIVE COOPERATIVTY O

24
Q

pO2 in lungs

A

98%

25
Q

pO2 in tissues

A

20%

26
Q

When Hb comes to our tissue, O2 will be delivered. Why is that

A

This is due to changes in our pH.
Actively metabolizing tissue has a pH of 7.2. This is lower than normal.

Decrease pH= (high H+ ions and high CO2), the Hb’s affinity for O2 will decrease and O2 will be delivered to the tissue.

His 146 will then come and pick up H+ ions

27
Q

Decrease in pH causes what?

A

low pH means that there are alot of (H+ ions and CO2).

His 146 will come and pick up H+ ions and deliver to the RBC

Hb affinity for O2 will drop and this will facilitate the release of O2 from our tissue/

28
Q

What picks up H+ ions to deliver to the RBC, which facilitates the release of O2

A

Histidine 146

29
Q

High CO2, ______ Hb’s affinity for O2

A

decreases

30
Q

Why does high CO2 decrease Hb’s affunity for O2

A

CO2 will eventually form H+

So when you see CO2 think of H

31
Q

high 2,3 BPG will do what to the affinity of O2.

A

High 2,3 BPG will cause Hb’s affinity for O2 to decrease

32
Q

In high altitudes, we have a decrease in pO2. How will our bodies production of 2,3 BPG change?

A

Our body will increase production of 2,3 BPG because it decreases Hb’s affinity for O2, causing O2 to be delivered to our tissue.

33
Q

High 2,3 BPG will cause a shift to the _____ in the ODC curve

A

RIGHT.

34
Q

while excerising, our pO2 ______

A

drops. Thus, Hb can deliver tissue.

35
Q

Fetal RBC have a lower/higher affinity for O2 than mothers Hb. Why?

A

Higher

Fetal RBC have a higher affinity for O2 than mothers because fetal RBC does not bind well to 2,3 BPG.

*Remember, 2,3 BPG will decrease the affinity.

36
Q

The higher affinity for O2 of fetal Hb allows what?

A

O2 to transfer from mother–> child.

37
Q

Fetal RBC do/do not bind well to 2,3 BPG, causing them to have a lower/ higher affinity to O2.

A

does not bind well
causing them to have a higher affinity to O2

Because 2,3 BPG decreases Hbs affinity for O2

38
Q

Iron travels in the blood as ______

A

transferrin

39
Q

Where does transferrin go?

A

RBCs are made in the bone marrow. Thus, transferrin will go to the bone marrow to provide the Fe, and create our

RBCs!!!!!

40
Q

Every ____ days, RBCs are broken down and release ____ and _____

A

Ever 120 days, RBCs are broken down by macrophages and release Hb and iron (as transferrin).

41
Q

Sites where iron travels

A
  1. intestines
  2. blood
  3. bone marrow
  4. eaten by macrophage and taken to liver
    then released bak into blood stream
42
Q

Where is the iron mostly located in our bodies?

A

67% of our iron is in hemoglobin
27% of our iron is stored
-ferritin (H20 soluble)
-hemosiderin (H20 insoluble)

43
Q

What are our storage forms of iron?

A

Ferritin

and hemosederin

44
Q

If ferritin water soluble or not?

A

Yes, ferritan is H20 soluble

45
Q

Is hemosiderin H20 soluble or not?>

A

No, H20 insoluble

46
Q

Fe2+

A

ferrous

47
Q

Fe3+

A

ferric

48
Q

Absorption of animal product heme iron

A

Animal product heme iron has (Fe2+: ferrous)

  1. Fe2+ goes inside of the enterocyte and is converted to ferric (Fe3+)
  2. Ferric is then converted to storage form ferritin (H20 soluble)
  3. Ferric can then be degraded to hemosiderin
49
Q

What are the 2 storage forms of Fe

A
  1. Ferritin (H2O soluble)

2. Hemosiderin (H2O insoluble)

50
Q

Plant products have what kind of iron?

A

Non-heme iron (Fe3+: Ferric)

51
Q

Can Fe3+ (ferric) be easily transported into the enterocyte?

A
No. It needs to be converted to Fe2+ using 
ferric reductase (duodenal cytochrome C).
52
Q

How does Fe2+ derived from Fe3+ enter the enterocyte?

A

Divalent transporter 1

53
Q

What happens to plant derived Fe2+ now that it is in the enterocyte?

A
  1. It can be converted to Fe3+ via ferroxidase and then go into the storage form.
  2. it can go into the blood via ferroportin
54
Q

Now that plant derive Fe2+ is in the blood, what happens?

A
  1. Converted to ferric (Fe3+) using ferroxidase/ceruloplasmin/haphaestrin
  2. Fe3+–> transferrin
55
Q

What allows plant derived Fe2+ to enter the blood stream?

A

ferroportin

56
Q

What converts Fe2+–> Fe3+

Ferrous–>ferric

A

Ferroxidase
Ceruloplasmin
Haphaestrin

57
Q

Other names for Ferroxidase

A

ceruloplasmin

Haphaestrin

58
Q

Plant Fe absorption pathway

A

Plants have non-heme iron: Fe3+ (called Ferric)

Fe3+ cannot be easily absorbed across the membrane. Thus, it must be converted to Fe2+

  1. Fe3+–> Fe2+ via [ferric reductase/duodenal cytochome C]. these are dependent on vitamin C
  2. Fe2+ is now taken inside of the enterocyte using divalent transporter I (DMT1)
  3. Once inside; two things can happen to Fe2+
    A. It can be converted to Fe3+ (ferric) and converted to
    storage forms (ferritin and hemosiderin) via
    ferroxidase/haphaestrin/ceruloplasmin
    B. It can be taken into the blood via [ferroportin]
4. Once in the blood
    A. Fe2+ is converted to Fe3+ via 
      [ferroxidase/haphaestrin/ceruloplasmin]. this is 
      dependent on Cu.
    B. Fe3+ is converted to transferrin
59
Q

What is the role of ferric reductase?

A

Ferric reductase will convert plant derived ferric (Fe3+) into Fe2+, which can more easily be transported into the enterocyte.

Dependent on vitamin C

60
Q

What is the role of divalent transporter 1 (DMT1)?

A

Transports plant derived Fe2+ into the enterocyte

61
Q

What is the role of ferroxidase, haphaestrin and ceruloplasmin?

A

The convert Fe2+ to Fe3+

Dependent on copper (Cu)

62
Q

What is the role of ferroportin?

A

Transports Fe2+ from the cell, into the blood

63
Q

Free iron is

A

Fe2+

ferrous

64
Q

Dietary iron is

A

Fe3+

ferric

65
Q

Where is transferrin taken?

A

Transferrin is taken to the spleen, liver, bone marrow but also the MITOCHONDRIA

66
Q

Transferrin transfer to the mitochondria

A

Transferrin wants to go here because thats where heme is made

Transferrin is uptaken by receptor-mediated endocytosis via tranferrin receptors (TfR)

It is enclosed in clatherin encoated vesicles and then delivered directly inside the mitochondria.
No transporter is necessary

67
Q

Is a transporter necessary to deliver transferring to the mitochondria?

A

Noo. transferrin is transferred directly inside

68
Q

Iron deficiency

A
  • result of a deficiency in dietary fiber (Fe3+)

- Most common in menstruating women and aspirin overuse

69
Q

Iron deficiency can cause

A

hypochromic microcytic anemia

70
Q

Tx of iron deficiency

A

dietary fiber supplement

71
Q

Hereditary hemochromatosis

A

Too much iron (15g) compared to normal (3-5g) due to a problem uptaking and exporting iron via enterocytes

Result: organ dysfx–> cirrhosis, arthritis, endocrinopathy

72
Q

Hepcidin

A

Hepcidin regulates levels of iron by having an affect on ferroportin.

When hepcidin increases, it causes the internalization and destruction of ferriportin, decreasing the amount of iron that leaves.

73
Q

Hepcidin structure

A

25 AA peptide that is made by the liver

74
Q

How does hepcidin affect levels of iron

A

when hepcidin is high, its does not let iron leave the cell. so it decrases blood iron levels

75
Q

When iron is high, what affect was hepcidin have

A

Hepcidin increase
Ferroportin decrease
Blood iron levels decrease

76
Q

When iron is low, what affect does hepcidin have?

A

Hepcidin levels are low
Ferroportin is high
Absorption if iron increases

77
Q

What is hepcidins receptor?

A

Ferroportin

78
Q

How are hepcidin levels controlled?

A

Hepcidin levels are controlled by transferrin levels.

  1. Transferrin will bind to receptors (Tfr1).
  2. Hfe gets transported to Tfr2
  3. Tfr2 is internalized and goes to the nucleus to turn the levels of hepcidin up

this prevents iron from leaving

79
Q

What happens if you have a mutation in [Hfe]?

A

mutation in [hfe]

prevents hepcidin from being activated
which means that ferroportin transporter will stay

which means that levels of blood iron will increase!

decrease hepsidin
increase ferriportin
increase blood Fe

80
Q

The production of RBCs depend on

A
folate
vitamin b12 (cobalamin)
81
Q

a decrease in vitb12 and folate lead to

A

megaloblastic macrocytic anemia

82
Q

Megaloblastic macrocytic anemia occurs when

A

we have a decrease in vitb12 or folate.
As RBCs are being produced in the bone marrow, dna synthesis is impaired

because folate is responsible for making DNA!!!!

83
Q

What do the RBCs of megaloblastic macrocytic anemia look like

A

Large RBC, but normal Hb content.

84
Q

Blood smear of someone with megaloblastic macrocytic anemia

A

large RBCs

oval macrocytes

85
Q

Bone marrow of someone with megaloblastic macrocystic anemia

A
large erythroblasts
hypersegmented neutrophils (like 5 lobes)
86
Q

Folate is also called

A

pteroglutamic acid

87
Q

Folate has ___ parts

A
  1. pteridine ring
  2. PABA
  3. glutamate
88
Q

what is the dietary form of folate

A

Dihydrofolate (DHF)

89
Q

What is the active form of folate

A

Tehtrahydrofolate (THF)

90
Q

How do we go from the dietary DHF–> to the active THF?

A

dihydrofolate reductase

91
Q

Importance of THF

A

Tetrahydrofolate is important in DNA synthesis!!!

it has more carbons so it serves asa ONE-CARBON donor

92
Q

FH2 is

A

dihydrofolate

93
Q

FH4 is

A

tetrahydrofolate

94
Q

THF serves as a _____-carbon donor

A

ONE-carbon donor for the synthesis of nucleotides

95
Q

Which part of folate metabolism is responsible for nucleotide synthesis

A

methenyl-THF

96
Q

Which part of the folate metabolism gets stuck?

A

methyl-THF

97
Q

How do we get methyl THF unstuck

A

it needs vitamin B12 (cobalamin) to make THF again!

98
Q

THF can become

A
  1. methnyl THF (nucleotide synthesis)
  2. N 5,10 methylene THF ( donates carbon to dUMP–>dTMP then converted back to DHF)
  3. methyl-THF gets stuck and needs vit B12 to remove methyl and make THF again! :)
99
Q

a decrease in folic acid can lead ________, which can cause _____________

A

a decrease in folic acid can lead to DECREASED DNA SYNTHESIS, which can lead to MEGALOBLASTIC MACROCYTIC ANEMIA

100
Q

folate metabolsim

A

folate–> DHF–>THF
THF can become three things
1. N5,10 methylene THF–> methyl THF
2. methynl THF (nucleotide synthesis

101
Q

Folate (DHF) is found

A

in most food like eggs, yeast and milk

102
Q

the main carbon transfer of folate occurs when

A

the main carbon transfer occurs

when the carbon side chain of serine is transferred to THF to form
N-5,10-methylene TFH

103
Q

Folic acid is absorbed in the ________

A

jejunum of the small intestine

104
Q

Once folic acid is absorbed in the small intestine, what happens?

A

it becomes methyl-THF. Thus, to activate it, it needs vitamin b12/cobalamin

105
Q

What is the primary circulating form of THF in the blood?

A

methyl-THF

thus, to free it we need to add vitamin b12 or cobalamin

106
Q

Why do we need vitamin b12

A

vitamin b12 is needed so that it can demethylate our methyl-THF and it can be freed into the blood.

addition of vitaminb12 makes [methyl-vitab12] to free our THF

107
Q

recommended daily allowance of vitamin b12 is

A

3ug

108
Q

B12 absorption

A

We intake vitamin b12

  1. B12 will bind to R-binder proteins in the stomach
  2. Parietal cells will secrete intrinsic factors
  3. Pancreas will release proteases, which will degrade R-binder proteins and release b12 in the duodunum
  4. b12 will bind to intrinsic factors and be taken to the ileum, where they are taken to the blood via receptor mediated endocytosis.
109
Q

where is folate absorbed at?

A

jejunum

110
Q

Where is b12 absorbed at?

A

ileum

111
Q

What method are folate and b12 absorbed with?

A

receptor mediated endocytosis

112
Q

cobalamin is carried in the blood via ______

A

transcobalamin

113
Q

Pernicious anemia

A

pernicious anemia is caused by a deficiency in vitamin b12.

this lack of b12 can be a result of lack of intrinsic factors

114
Q

is pernicious anemia a megaloblastic macrocystic anemia?

A

YES!!!!!

115
Q

to detect pernicious anemia?

A

SCHILLING TEST!