Hemoglobin Synthesis and Catabolism (McCormick)

Question 2

2 main components of hemoglobin

Answer 2

hemeglobin proteins. 2 pair chains

Question 3

heme structure

Answer 3

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

Question 4

what are the two distinct globin chains in hemoglobin

Answer 4

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

Question 5

rate limiting step of heme synthesis

Answer 5

ALA synthaseglycine + aminolevulinic acid

Question 6

Steps of heme synthesis and where do they take place

Answer 6

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

Question 7

Formation of protoporphyrin ring?

Answer 7

condensation of 4 PBG in cytosol

Question 8

Where does Fe join with heme?

Answer 8

in the mitichondria

Question 9

Mutation of ALA synthase?

Answer 9

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

Question 10

What mutations cause porphyria and what are symptoms?

Answer 10

ALA dehydrase and PBG synthaseaccumulation of substrate on skin- extremely photosensitive. Urine is red

Question 11

Pb poising inhibits what enzymes

Answer 11

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

Question 12

Where does globin synthesis take place

Answer 12

cytoplasm of normoblasts and reticulocytes(immature RBC)

Question 13

What stimulates globin synthesis

Answer 13

increase of heme availability

Question 14

where are alpha chains gene located

Answer 14

chromosome 16

Question 15

where are beta chains gene located

Answer 15

chromosome 11

Question 16

thalassemia

Answer 16

unbalanced gene expression of the globin chains for hemoglobin

Question 17

What is required for the combination of heme and globin

Answer 17

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 18

HbF

Answer 18

2 alpha and 2 gamma

Question 19

Hb A2

Answer 19

2 alpha and 2 delta.

Question 20

During gestation what Hb are most common

Answer 20

alpha chain, and gamma chaingower chain lasts till about 3 mo

Question 21

Describe Hb production at birth

Answer 21

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

Question 22

Deoxyhemoglobin

Answer 22

reduced hemoglobin. not carrying O2

Question 23

Oxyhemoglobin

Answer 23

hemoglobin carrying O2, can be measured by pulse oximetry

Question 24

Red pulse oximetry

Answer 24

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 25

MetHb

Answer 25

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 26

Methemoglobin reductase

Answer 26

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

Question 27

Sulhemoglobin

Answer 27

oxidized partially denatured Hb--> may result in RBC destruction and hemolysiscannot carry O2this is not usually present!formed from sulfur-containing drugs or aromatic amine drugs

Question 28

CarboxyHb

Answer 28

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

Question 29

Fe2+ bonds in functional hemoglobin

Answer 29

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

Question 30

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

Answer 30

primarily diet.we have heme and nonheme

Question 31

non heme Fe

Answer 31

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 32

Ferroportin (aka mobilferrin)

Answer 32

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

Question 33

hemachromatosis

Answer 33

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

Question 34

Heme iron

Answer 34

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 35

how is Fe3+ converted to Fe2+ for heme iron

Answer 35

enterocytes

Question 36

How do we store Fe

Answer 36

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

Question 37

RBC destruction

Answer 37

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

Question 38

Where does RBC get energy

Answer 38

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

Question 39

how does spleen get rid of RBC

Answer 39

phagocytosis in specific macrophages found in spleen sinusoids

Question 40

polycythemia

Answer 40

RBC synthesis is greater than destruction

Question 41

anemia

Answer 41

RBC destruction greater than synthesis

Question 42

Hemoglobinemia (plasma) of hemoglobinuria (urine)

Answer 42

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

Question 43

Hb desctruction

Answer 43

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 44

what does protoporphyrin get recycled as

Answer 44

biliverdin --> bilirubin

Question 45

HbS

Answer 45

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

Question 46

Thalassemia : quantitative defect

Answer 46

quantitative defect, not enough producedheterozygote resistance to malaria

Question 47

microcytic hypochromic anemia

Answer 47

underproduced globin chainsmicrocytic (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 48

alpha thalassemia? give examples (x2)

Answer 48

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

Question 49

Beta thalassemia? give examples

Answer 49

excess of alpha chains. or elevated HbF or A2B- thalassemia minor- heterozygous disorderB-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 50

Beta thalassemia signs

Answer 50

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 51

ALA synthase

Answer 51

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

Question 52

PBG synthase

Answer 52

also known as ALA Dehydrataselocated in the cytosolcatalyzes condensation of two molecules of ALA to form PBG (porphobilinogen)

Question 53

Ferrochelatase

Answer 53

inserts iron into protoporphyrin in the mitochondria to form heme

Question 54

As oxygen partial pressure increases...

Answer 54

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

Question 55

hepcidin

Answer 55

controls expression of ferroportinif hepcidin attaches to ferroportin causes it to disintegrate and internalize into the cellregulates iron absorption by decreasing absorption of iron by intestine

Question 56

heme oxygenase

Answer 56

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

Question 57

appoferritin

Answer 57

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

Question 58

heme oxygenase (oxidase)

Answer 58

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

Question 59

Sickle Cell Disease

Answer 59

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

Question 60

Symptoms of Cooley's anemia

Answer 60

HepatosplenomegalyProminent 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'sRBC's are overproduced which expand the marrow spaces in bone "hair on end" due to new bone formation