Lec 10 Erythrocyte Biochem Flashcards
Erythropoiesis steps
What are the subunits on hemoglobin?
2 alpha globin chains
2 beta globin chains
how many heme per subunit?
What form of iron in heme?
Function and characteristic of heme?
1
Ferrous Fe2+
Carries O2 and is hydrophobic
Types of heme?
Embryonic
fetal
adult
Embryonic heme
Gower and portland up to 8 weeks (embryo)
Fetal hemoglobin heme type and presence
HbF (alpha gamma)
At 10 weeks alpha and gamma rise gamma fall near birth
Adult heme and presence
HbA aplpha and beta
beta rises around birth alpha already present
Hb A2 rarer
sickle cell anemia heme and research
Hbs
research ongoing to induce expression of HbF
(hydroxyurea)
What binds to heme?
F8 histidine
(proximal histidine)
What stabalizes bond between heme and O2
Distal histamine (E7)
Conformational change
Myoglobin oxygen dissociation curve?
hyperbolic more to the left
Hemoglobin oxygen dissociation curve shape?
sigmoidal (due to interactions between subunits)
Cooperativity in hemoglobin
Oxygen dissociation curve (release of O2)
Bohr Effect
pH of active tissues lower
binding affinity decreases with pH
histidine is bound with H+
conformation chang of Hb favors O2 release
2,3 bisphosphoglycerate
reduces 02 affinity so Hb gives up O2 to tissues
signal Hb to let go of O2
the curve and exercise
has pO2 drop from 40 to 20 torr which is steepest part of curve so very effective in providing oxygen to tissues
The curve and HbF and HbA
Fetus needs Hb that has higher affinity for O2 than mothers (left shift)
HbF does not bind well to 2,3 BPG (cause for affinity diff)
Iron cycle basic process
Iron distribution
Hemoglobin 67%
storage iron 27%
ferritin-H20 sol
hemosiderin-H20 insol
Myoglobin 5%
Fe-requiring proteins 1%
Iron from intestinal lumen to Enterocyte
Heme just goes through ferroxidase to Ferrous iron (Fe 2+)
ferric iron (3+) is converted into ferrous iron via Duodenal cytochrome B
Fe2+ then goes through DMT1
(divalent transporter 1)
FRom enterocyte to blood Fe
Fe2+ leaves via ferroportin
Storage in enterocyte of Fe
Fe2+ to Fe3+ then stored in ferritin
which can be degraded to hemosiderin
Free Fe2+ in blood?
ferroxidase helps Fe2+ to Fe3+ which is transported by transferrin to tissues
When transferin reaches cells?
uptake occurs by receptor mediated endocytosis (transferin receptor)
Mitochondria uptake (heme made here) effecient
DMT1 transports iron out of endosome
Hypochromic microcytic anemia
low iron
less iron that are smaller
treatment is dietary iron supp
Iron deficiency causes
diet iron low
menstruating women
aspirin overuse
ulcers of GI
Hereditary hemochromatosis
Iron overload organs: cirrhosis arthritis
cardiomyopathy
3 to 5 g normal here 15g
treatment blood letting
Role of Hepcidin
binds to ferroportin which causes internalization of ferroportin
ferroportin destroyed by proteolysis
Iron levels and hepcidin
iron is high? hepcidin expression up ferroportin levels down, iron absorption low
When iron is low? hepcidin down ferroportin up iron absorption high
regulation of hepcidin expression
Hfe is supposed to bind Tfr2 which turns on expression of hepcidin
if Hfe is mutated it will not and no hepcidin so no control of ferroportin activity (increased iron)
RBC production dependent on what?
vit B12 and Folate (folic acid)
deficiency in B12 and folate leads to what?
megaloblastic anemia (Due to DNA synthesis impairment in bone marrow)
Megaloblastic macrocytic anemia
deficiency in B12 and folate
large erythrocytes with normal hemoglobin content
Megablastic macrocytic anemia Pic
Changes in bone marrow in megaloblastic macrocytic anemia
How many parts does folic acid have?
3 parts
Folate in the diet comes in as? what does it need to become? what catalyzes this?
Main function of tetrahydrofolate (THF)
a one carbon donor for synthesis of nucleotides
uses 2 N
Tetrahydrofolate (THF) and carbon
THF gets carbon side chain of serine changes to N5,10-methylene-THF which transfers carbon to deoxyuridylate forms dTMP
Folic acid is absorbed where?
small intestine jejunum
What stores folic acid?
liver stores 5-10 mg which can last 3 to 6 months
primary form of folic acid in bloodstream?
N5 methyl THF
B12 and folate
N5 methyl THF requires vitamin B12 (cobalamin) to become demethylated (or else it is stuck as N5)
creates methyl-cobalamin release THF
Vit b12 is from what? deficiency?
not in plant products
deficiency is very rare
B12 absorption
R-binder proteins (gastric mucosa) bind B12
R-binder degraded by proteases in duodenum
intrinsic factor carries B12 to ileum where receptors bring into body
how is intrinsic factor-cobalamin absorbed?
VIA RECEPTOR MEDIATED ENDOCYTOSIS
Pernicious Anemia
Schilling test part 1
Schilling Test part two
