39: Hemoglobin - Schmidt Flashcards
most abundant form of hemoglobin in adults
HbA
a2b2
compromise 97% of total hemoglobin in adults
t or f: the four heme subunits bind O2 with equal affinity
false
Hb does not bind O2 efficiently at ____ 02 concentration
low
as O2 levels increase, Hb becomes more efficient at binding O2
this gives a sigmoid shape to the binding curve
see slide 3
________ binds O2 with high affinity at low O2 concentration
myoglobin
the binding curve is hyperbolic
see slide 3
fetal hemoglobin =
early in embryonic development…
Hb gower 1 =
Hb gower 2 =
Hb Portland L2Y2 =
a2g2
z2e2
a2e2
z2g2
gower and portland need to capture O2 from mom and have VERY high oxygen affinity
as development progresses …. reciprocal switch from _ chain synthesis to _ chains synthesis
gamma chain to beta chain
a histidine residue in b-chain required for 2,3-BPG binding is replaced with serine in the g-chain (reduces 2,3 affinity and increases oxygen affinity)
leads to replacement of HbF with HbA
HbF comprises less than 2% of total Hb by the end of the first year of life
look at slide 4 / 5
a like globins =
b like globins =
a and z (chromosome 16)
b, g, d, e (chromosome 11)
HS-40 is upstream of…
LCR is upstream of…
a-like on chrm 16
b-like on chrm 11
these upstream regulatory elements confer high-level, tissue specific expression
what is EKLF? erythroid kruppel-like factor
expression increases b-globin gene expression
involved in g–>b globin gene switchin
heinz bodies indicated –>
unstable hemoglobins
often form hemichrome and precipitate as heinz bodies
Hb helsinki
b-subunit mutation at 2,3BPG binding site –> increased oxygen affinity
Hb kansas
b-subunit mutation at a2b2 contact site –> decreased oxygen affinity
Hb Mboston
alpha subunit mutation that causes a structural variant that readily form methemoglobin
Hb Mhyde park
beta subunit mutation that causes a structural variant that readily form methemoglobin
glutamate replaced with valine at position six of b-globi chain –>
Hb S (sickle cell disease)
deoxygenated HbS will polymerize! —> distort RBC shape, circulation block, lysis (chronic hemolytic anemia)
heterozygote = trait homozygote = disease
treatment of choice in adults with sickle cell
hydroxyurea
increases the expression of HbF –> promotes hemoglobin solubility and reduces sickling, painful crises, hospializations
unknown MOA
glutamate replaced with lysine at position six of b-globin chain
*only west african origin
HbC
Hb C is less soluble than HbA and precipitates
–> less flexible red cells have reduced lifespan (hemolytic anemia)
Hb SC =
milder than Hb S disease
glutamate at position 26 of b-globin chain is replaced with lysine
HbE
common in southeast asia (mild anemia and microcytosis only if homozygotes)
–> b-globin chain is not synthesized effectively –> thalassemia
reduced synthesis of either type of chian reduces amount of functional tetramer formed =
thalassemia
a/b thalassemias vs. a/b+ thalassemias
no functional globin chain produced
reduced amount of globin chain produced
a-thlassemias manifest…
during development and in adult life
there are 4 genes for alpha –> lose more = more severe disease
bart’s hemoglobin
gama4 tetramers form in fetus
poor oxygen carriers
due to only 1 functional a globin gene
Hb H
b4 tetramers
poor oxygen carriers
precipitates shortening red cell life
due to only 1 functional a globin gene
hemoglobin bart’s hydrops fetalis syndrome
only embryonic hemoglobins produced to to 4 defective a-globin genes
lethal condition
a-thalssemias most often arise by …
deletion by homologous recombination
Hb constant spring
T replaced by C pt mutation
a-globin chain length increased from 141-> 172 aa
looks like a a+ thalssemia because unstable
lepore hemoglobin
delete part both b and d globin genes
functions poorly as a globin chain
how many b genes?
one
b-globin gene defects have phenotypes depending on residual abilities left
screening techniques for hemoglobinopathies
isoelectric focusing(any hemoglobinopathy) or PCR-RFLP(only sickle cell) in neonatal screenings
the low O2 environment of the tissue favors…
the high O2 environment of the lungs favors …
dissociation
binding
binding of 2,3 BPG favors…
oxygen dissociation
