Erythrocyte Biochem Flashcards
Erythropoiesis
-starts as stem cell
• Majority of Hb synthesized before extrusion of nucleus
• Small amount made in reticulocyte
hemoglobin structure
• Multi-subunit
protein (tetramer)
– 2 a-globin chains
– 2 b-globin chains
heme
– One per hemoglobin subunit – Has iron atom (ferrous : Fe2+) – Carries O2 – Hydrophobic
Embryonic hemoglobin
Hb Gower 1 (]2epislon2)
Hb Gower 2 (a2epsilon2)
Hb Portland (]2gmma2)
fetal hemoglobin
Hb F (a2gamma2), 0.5%
adult hemoglobin
Hb A (a2b2), 97% Hb A2(a2G2), 3%
what are chains of hemoglobin derived from?
diff genes located on diff chromosomes (16 and 11)
treatment for sickle cell anemia
induce expression of HbF
using hydroxyurea
but this is a toxic
chemotherapeutic agent
what is the proximal histidine
The F8 histidine (bound to heme)
what is the distal histidine
The E7 histidine
where does O2 bind?
binds to the iron between the heme and distal histidine
what is the conformation change when O2 binds?
pulls down the proximal F8 histidine of Hb and
changes interaction with associated globin chain
what kind of curve is myoglobin
hyperbolic
what kind of curve is hemoglobin
sigmoidal (due to interactions between globin subunits)
positive cooperativity
- Binding of one molecule of O2 to one heme, facilitates the
binding of an O2 to another heme
-Conformational change in one globin subunit induces a
conformational change in another subunit in Hb - The binding of O2 to Fe of a globin subunit pulls the proximal
F8 histidine down - This pulls on the globin FG-helix and changes the interaction
with the other globin chains in Hb
Bohr Effect
decrease in Ph causes binding affinity of Hb for O2 to decrease (right shift)
-causes release of o2
2,3-BPG
- causes right shift
- reduces O2 affinity so Hb gives up more O2 to tissues
effects of o2 on ODC
drop in P02 from 40 to 20 torr
why does HbF have higher O2 affinity than HbA
Hbf does not bind well to 2,3 BPG therefore has higher affinity for O2
in what form is iron stored?
Fe 3+ (ferric)
in what form is iron transfered in blood
Fe3+
how does nonheme iron enter enterocyte?
ferric reductase converts to Fe2+
-Fe 2+ enters enterocyte through divalent transporter-1(DMT1)
what converts Fe 2+ to Fe 3+
hephaestin/ cerruloplasmin/ ferroxidase
what converts Fe 3+ to Fe 2+
Dcytb (duodenal cytochrome like B) aka ferric reductase
what allows Fe2+ to go from enterocyte to blood
ferroportin
how is transferin uptaken from blood?
occurs by receptor-
mediated endocytosis via transferin receptor (TfR)
what transports iron out of edosome?
DMT1
what causes Causes hypochromic microcytic anemia
Insufficient dietary iron
Menstruating women
Aspirin overuse
Ulcers of GI tract (Blood loss)
what is treatment for hypochromic microcytic anemia
dietary iron supplementation
Hereditary Hemochromatosis
Organ dysfunction due to iron overload: cirrhosis, arthritis, endocrinopathy, skin pigmentation, cardiomyopathy
what is total body iron inHereditary Hemochromatosis compared to normal
› 3 to 5g normal
› Hereditary Hemochromatosis = 15g
Hepcidin
binds to ferroportin and causes internalization
-regulates amount of Fe taken up by body
how is hepcidin expression regulated
by Hfe binding to TfR2
what happens if Hfe is mutated and can’t bind to TfR2
- cant turn on hepcidin expression
- lots of ferroportin
- iron overloading
what vitamins are required for RBC production
vitamin B12 (cobalamin) and folate (folic acid)
what does deficiency in B12 and folate cause?
megaloblastic anemia
-due to diminished synthesis of DNA
Megaloblastic Macrocytic Anemia
Caused by vitamin B12 (cobalamin) and folate (folic acid)
deficiency
Characterized by large erythrocytes
› MCV >100 fL (as high as 140 fL); normal = 80-100
**NORMAL HEMOGLOBIN CONTENT
what disease to hyper-segmented neutrophils occur?
Megaloblastic Macrocytic
Anemia:
what is the structure of folate?
3 parts:
– Pteridine: nitrogen containing ring
– p-amino-benzoic acid ring (PABA)
– Glutamate residue chains
what is the active form of folate?
THF (FH4) (tetrahydrofolate)
what is the role of THF (FH4)(tetrhydrofolate)
transfer of carbon units from donor to acceptors (vital role in DNA synthesis)
what is the form of dietary folic acid?
FH2 (dihydrofolate)
where is folate absorbed
small intestine (jejunum)
what organ stores folate?
liver
-stores 5-10 mg folate lasts 3-6 months
what is primary circulating form of folate?
N5-
methyl-THF
what happens if B12 not available for folate?
folate stuck
as N5-methyl-THF : called the folate
trap
what does vit b12 do to folate?
removes methyl group from N5-methyl-THF to
make methyl-cobalamin (B12-CH3) and release THF (FH4)
what does dietary B12 bind to?
R-binder proteins made by gastric mucosa cells
what carries b12 to ileum
intrinsic factor made by parietal cells of stomach
Pernicious Anemia
Vitamin B12 deficiency can occur due to lack of intrinsic factor
(necessary for B12 absorption)
- ms a megaloblastic macrocytic anemia
how is pernicious anemia diagnosed
schilling test
