Hemoglobin Synthesis and Catabolism (McCormick)

Question 1

2 main components of hemoglobin

Answer 1

heme

globin proteins. 2 pair chains

Question 2

heme structure

Answer 2

have 4 N bonds to attach to Fe.
Porphyrin ring.
4 hemes per molecule

Question 3

what are the two distinct globin chains in hemoglobin

Answer 3

alpha and non-alpha(because can be many different types)

Question 4

rate limiting step of heme synthesis

Answer 4

ALA synthase

glycine + aminolevulinic acid

Question 5

Steps of heme synthesis and where do they take place

Answer 5

1) form porphobilinogen via ALA synthase(mitochondria) and PBG synthase (cytosol)
2) form heme from protoporphyrin ring and Fe (mitochondria)

Question 6

Formation of protoporphyrin ring?

Answer 6

condensation of 4 PBG in cytosol

Question 7

Where does Fe join with heme?

Answer 7

in the mitichondria

Question 8

Mutation of ALA synthase?

Answer 8

Sideroblastic anemia, no heme to insert Fe into. so Fe accumulates and precipitates in granules outside RBC (demonstrate ringed sideroblasts)

Question 9

What mutations cause porphyria and what are symptoms?

Answer 9

ALA dehydrase and PBG synthase

accumulation of substrate on skin- extremely photosensitive. Urine is red

Question 10

Pb poising inhibits what enzymes

Answer 10

ALA dehydrase and ferochelatase
accumulation of products
causes basophilic stipling (see lots of purple dots b/c accumulation of products)

Question 11

Where does globin synthesis take place

Answer 11

cytoplasm of normoblasts and reticulocytes(immature RBC)

Question 12

What stimulates globin synthesis

Answer 12

increase of heme availability

Question 13

where are alpha chains gene located

Answer 13

chromosome 16

Question 14

where are beta chains gene located

Answer 14

chromosome 11

Question 15

thalassemia

Answer 15

unbalanced gene expression of the globin chains for hemoglobin

Question 16

What is required for the combination of heme and globin

Answer 16

1. adequate supply of Fe.
2. Normal Heme synthesis, leaves mitochondria.
   join in cytoplasm.
3. Normal globin synthesis (in cytoplasmic ribosomes) Hb in adult have two alpha, two beta

Question 17

HbF

Answer 17

2 alpha and 2 gamma

Question 18

Hb A2

Answer 18

2 alpha and 2 delta.

Question 19

During gestation what Hb are most common

Answer 19

alpha chain, and gamma chain

gower chain lasts till about 3 mo

Question 20

Describe Hb production at birth

Answer 20

gamma chain drops rapidly for 6 months and Beta chain increases rapidly for 6 months
delta slowly slowly increases

Question 21

Deoxyhemoglobin

Answer 21

reduced hemoglobin. not carrying O2

Question 22

Oxyhemoglobin

Answer 22

hemoglobin carrying O2, can be measured by pulse oximetry

Question 23

Red pulse oximetry

Answer 23

deoxyHb and OxyHb absorb light at different wavelengths, we can measure the difference and compute how much oxygen you have on board (your saturation)

Question 24

MetHb

Answer 24

hemoglobin carrying ferric iron (Fe3+) loses ability to bind O2 (usually less than 3% of total hgb)
usually caused by oxidizing drugs (nitrites or sulfonamides)

Question 25

Methemoglobin reductase

Answer 25

convert metHb back to Hb. This is a protective enzyme of RBC's

Question 26

Sulhemoglobin

Answer 26

oxidized partially denatured Hb--> may result in RBC destruction and hemolysis cannot carry O2 this is not usually present! formed from sulfur-containing drugs or aromatic amine drugs

Question 27

CarboxyHb

Answer 27

carrying CO produced during heme degradation to bilirubin | elevated levels of CarboxyHb in people with CO poisoning.

Question 28

Fe2+ bonds in functional hemoglobin

Answer 28

four to attach to heme, one attaches to globin chain and one binds (reversibly) to O2

Question 29

Where is the Fe to be inserted into heme coming from ?

Answer 29

primarily diet. | we have heme and nonheme

Question 30

non heme Fe

Answer 30

from diet primarily. Ferrous form absorbed most readily, so Fe3+ must be reduced by ferric reductase. Dcytb. DMT1 cotransports Fe2+ and H+ in cell, minds mobilferrin (ferroportin) to be transported

Question 31

Ferroportin (aka mobilferrin)

Answer 31

basolateral membrane protein that binds Fe2+ and and allows the Fe2+ to enter the blood expressed by a gene, regulated by hepcidin

Question 32

hemachromatosis

Answer 32

iron overload. can give the pt's chelating proteins to bind Fe and prevent the overload

Question 33

Heme iron

Answer 33

from breakdown of meats and RBCs in body. absorbed by duodenal epithelium via binding or endocytosis. Intracell: heme oxygenase splits heme and releases free Fe3+

Question 34

how is Fe3+ converted to Fe2+ for heme iron

Answer 34

enterocytes

Question 35

How do we store Fe

Answer 35

In spleen and liver, absorbed in duodenum. | apoferritin takes up Fe for storage

Question 36

RBC destruction

Answer 36

120 days in circulation. then called senescent RBCs, spleen takes them out of circulation (2-3 million cells per day)

Question 37

Where does RBC get energy

Answer 37

without mitochondria they use glycolysis and pentose phosphate cycle (HMP shunt)

Question 38

how does spleen get rid of RBC

Answer 38

phagocytosis in specific macrophages found in spleen sinusoids

Question 39

polycythemia

Answer 39

RBC synthesis is greater than destruction

Question 40

anemia

Answer 40

RBC destruction greater than synthesis

Question 41

Hemoglobinemia (plasma) of hemoglobinuria (urine)

Answer 41

intravascular hemolysis of RBCs form hemolytic anemia, autoimmune processes, transfusion reactions. This causes free Hb in plasma and urine leading to nephrotoxicity (which is damaging to the kidneys)

Question 42

Hb desctruction

Answer 42

macrophages in RES system degrade hemoglobin into 3 components: 1) Fe (goes to storage for reutilization) 2) Protoporphyrin (converted to bilirubin) 3) Globin (converted to aa's, recycled)

Question 43

what does protoporphyrin get recycled as

Answer 43

biliverdin --> bilirubin

Question 44

HbS

Answer 44

at position 6, glutamic acid has been replaced by valine due to missense mutation of Beta globin chain results in production of HbS Heterozygous vs. Homozygous At six months Hgb S replaces Hgb F (instead of Hgb A replacing Hgb F, which normally happens at six months)

Question 45

Thalassemia : quantitative defect

Answer 45

quantitative defect, not enough produced | heterozygote resistance to malaria

Question 46

microcytic hypochromic anemia

Answer 46

underproduced globin chains microcytic (small cell) hypochromic (does not stain as dark "ghost cells" prominent target cells on peripheral smear (looks just like a bullseye) Decrease in MCV (mean corpuscular volume) and MCH (mean corpuscular hemoglobin, or amount of hemoglobin per cell) hemoglobin A is usually decreased

Question 47

alpha thalassemia? give examples (x2)

Answer 47

overabundance of beta or gamma chain Examples: Hb H disease (lose 3 of the 4 alpha genes) results in beta tetramers Thalassemia major (lose all 4 alpha genes producing tetramer of gamma globin- results in hydrops fetalis with hepatosplenomegaly - die in utero this type of hemoglobin can't carry oxygen so die of anoxia

Question 48

Beta thalassemia? give examples

Answer 48

excess of alpha chains. or elevated HbF or A2 B- thalassemia minor- heterozygous disorder B-thalassemia major- homozygous disorider, resulting in cooley's anemia. show target cells on smear. overabundance of membrane for the amount of hemoglobin and cells collapse on themselves, so can only see hemoglobin on inside and outside of cell. (bullseye)

Question 49

Beta thalassemia signs

Answer 49

producing so much RBCs, cause expansion of marrow spaces--> pushes out bones. "hair-on-end" on skull radiograph (looks like hair) note--> B-thalaseemia is endemic in certain populations throughout europe and africa

Question 50

ALA synthase

Answer 50

located in the mitochondria takes succinyl CoA + glycine and makes ALA (condensation rxn) Rate limiting enzyme inhibiting by heme feedback system, which represses transcription of the gene for ALA synthase

Question 51

PBG synthase

Answer 51

also known as ALA Dehydratase located in the cytosol catalyzes condensation of two molecules of ALA to form PBG (porphobilinogen)

Question 52

Ferrochelatase

Answer 52

inserts iron into protoporphyrin in the mitochondria to form heme

Question 53

As oxygen partial pressure increases...

Answer 53

each of the four heme groups binds one molecule of oxygen (more ability of the hemoglobin to bind oxygen)

Question 54

hepcidin

Answer 54

controls expression of ferroportin if hepcidin attaches to ferroportin causes it to disintegrate and internalize into the cell regulates iron absorption by decreasing absorption of iron by intestine

Question 55

heme oxygenase

Answer 55

splits heme iron into free Fe3+ | this is located inside the epithelium cell

Question 56

appoferritin

Answer 56

storage protein in RES that is the iron buffer system | helps convert iron from transferrin the plasma to ferritin (storage form of iron)

Question 57

heme oxygenase (oxidase)

Answer 57

located in the macrophage of RES | breaks down porphyrin ring to CO and biliverdin

Question 58

Sickle Cell Disease

Answer 58

HgS this disease causes hemoglobin to be susceptible to polymerization at low oxygen concentrations Reduces flexibility of RBC membrane "sickling" of RBC's results these sickled cells can't get through capillaries and causes "crises or occlusions" resulting in hypoxic tissue injury

Question 59

Symptoms of Cooley's anemia

Answer 59

Hepatosplenomegaly Prominent protruding forehead and flattened nose b/c pt does not have enough oxygen carrying ability so the body thinks it is starving for oxygen so it produces more RBC's RBC's are overproduced which expand the marrow spaces in bone "hair on end" due to new bone formation