Hemoglobin Synthesis and Catabolism (McCormick) Flashcards
2 main components of hemoglobin
heme
globin proteins. 2 pair chains
heme structure
have 4 N bonds to attach to Fe.
Porphyrin ring.
4 hemes per molecule
what are the two distinct globin chains in hemoglobin
alpha and non-alpha(because can be many different types)
rate limiting step of heme synthesis
ALA synthase
glycine + aminolevulinic acid
Steps of heme synthesis and where do they take place
1) form porphobilinogen via ALA synthase(mitochondria) and PBG synthase (cytosol)
2) form heme from protoporphyrin ring and Fe (mitochondria)
Formation of protoporphyrin ring?
condensation of 4 PBG in cytosol
Where does Fe join with heme?
in the mitichondria
Mutation of ALA synthase?
Sideroblastic anemia, no heme to insert Fe into. so Fe accumulates and precipitates in granules outside RBC (demonstrate ringed sideroblasts)
What mutations cause porphyria and what are symptoms?
ALA dehydrase and PBG synthase
accumulation of substrate on skin- extremely photosensitive. Urine is red
Pb poising inhibits what enzymes
ALA dehydrase and ferochelatase
accumulation of products
causes basophilic stipling (see lots of purple dots b/c accumulation of products)
Where does globin synthesis take place
cytoplasm of normoblasts and reticulocytes(immature RBC)
What stimulates globin synthesis
increase of heme availability
where are alpha chains gene located
chromosome 16
where are beta chains gene located
chromosome 11
thalassemia
unbalanced gene expression of the globin chains for hemoglobin
What is required for the combination of heme and globin
- adequate supply of Fe.
- Normal Heme synthesis, leaves mitochondria.
join in cytoplasm. - Normal globin synthesis (in cytoplasmic ribosomes) Hb in adult have two alpha, two beta
HbF
2 alpha and 2 gamma
Hb A2
2 alpha and 2 delta.
During gestation what Hb are most common
alpha chain, and gamma chain
gower chain lasts till about 3 mo
Describe Hb production at birth
gamma chain drops rapidly for 6 months and Beta chain increases rapidly for 6 months
delta slowly slowly increases
Deoxyhemoglobin
reduced hemoglobin. not carrying O2
Oxyhemoglobin
hemoglobin carrying O2, can be measured by pulse oximetry
Red pulse oximetry
deoxyHb and OxyHb absorb light at different wavelengths, we can measure the difference and compute how much oxygen you have on board (your saturation)
MetHb
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)
Methemoglobin reductase
convert metHb back to Hb. This is a protective enzyme of RBC’s
Sulhemoglobin
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
CarboxyHb
carrying CO produced during heme degradation to bilirubin
elevated levels of CarboxyHb in people with CO poisoning.
Fe2+ bonds in functional hemoglobin
four to attach to heme, one attaches to globin chain and one binds (reversibly) to O2
Where is the Fe to be inserted into heme coming from ?
primarily diet.
we have heme and nonheme
non heme Fe
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
Ferroportin (aka mobilferrin)
basolateral membrane protein that binds Fe2+ and and allows the Fe2+ to enter the blood
expressed by a gene, regulated by hepcidin
hemachromatosis
iron overload. can give the pt’s chelating proteins to bind Fe and prevent the overload
Heme iron
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+
how is Fe3+ converted to Fe2+ for heme iron
enterocytes
How do we store Fe
In spleen and liver, absorbed in duodenum.
apoferritin takes up Fe for storage
RBC destruction
120 days in circulation. then called senescent RBCs, spleen takes them out of circulation (2-3 million cells per day)
Where does RBC get energy
without mitochondria they use glycolysis and pentose phosphate cycle (HMP shunt)
how does spleen get rid of RBC
phagocytosis in specific macrophages found in spleen sinusoids
polycythemia
RBC synthesis is greater than destruction
anemia
RBC destruction greater than synthesis
Hemoglobinemia (plasma) of hemoglobinuria (urine)
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)
Hb desctruction
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)
what does protoporphyrin get recycled as
biliverdin –> bilirubin
HbS
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)
Thalassemia : quantitative defect
quantitative defect, not enough produced
heterozygote resistance to malaria
microcytic hypochromic anemia
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
alpha thalassemia? give examples (x2)
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
Beta thalassemia? give examples
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)
Beta thalassemia signs
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
ALA synthase
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
PBG synthase
also known as ALA Dehydratase
located in the cytosol
catalyzes condensation of two molecules of ALA to form PBG (porphobilinogen)
Ferrochelatase
inserts iron into protoporphyrin in the mitochondria to form heme
As oxygen partial pressure increases…
each of the four heme groups binds one molecule of oxygen (more ability of the hemoglobin to bind oxygen)
hepcidin
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
heme oxygenase
splits heme iron into free Fe3+
this is located inside the epithelium cell
appoferritin
storage protein in RES that is the iron buffer system
helps convert iron from transferrin the plasma to ferritin (storage form of iron)
heme oxygenase (oxidase)
located in the macrophage of RES
breaks down porphyrin ring to CO and biliverdin
Sickle Cell Disease
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
Symptoms of Cooley’s anemia
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
