The Hill Equation
Ys = (P02)nH / { (P50)nH + (P02)nH }
Sickle Cell Disease is significant only in ___________state
homozygous
Where does heme synthesis occur?
Bone marrow
Haldane Effect
CO2_______ affinity of Hb for oxygen
CO2 stabilizes ___________ by reacting with terminal amino groups to form _______; these induce T-state
CO2 also stabilizes deoxy-Hb by causing a_______
Lowers
deoxyhemoglobin; carbomates
pH drop
2,3-BPG binding lowers O2 affinity by_________T-state
Stablizing
Major hemoglobins in adults
Alpha, beta, delta, and gamma
Sickle cell disease is caused by mutation in gene for_________ subunit of adult hemoglobin (Hb)
B
Myoglobin Hemoglobin
O2 ______ protein O2_________ protein
Location? Location?
of Hemes? # of Hemes?
of Globin Chains? # of Globin Chains
Allosteric effectors? Allosteric effectors? ________ Curve _________ Curve
Storage; carrier
Muscle; erythrocyte
1; 4
1; 4
None; H+,CO2 2,3-BPG, Cl-
Hyperbolic; sigmodial
Major hemoglobins in embryonic state
Zeta, alpha, gamma, and epsilon
Symptoms of Sickle cell disease
anemia
swelling of extremities
higher risk of stroke and infection
CO Inhalation leads to nonfunctional ___________ and _________hypoxia, pO2 may be normal but ______is high.
Hb; tissue; lactic acid
When are symptoms of Sickle Cell Disease seen?
Symptoms not seen until 6 months after birth
BPG-induced shifts O2 dissociation curve to the ________
Right
Does adult hemoglobin or fetal hemoglobin have a higher O2 affinity?
Fetal hemoglobin
In blood, ___________is a major target for CO poisoning
Hemoglobin
- Interactions with _________must be broken for T-to-R transition to occur
- When 2,3-BPG is present, more __________ sites must be occupied to induce transition
Gamma subunit of HbF lacks _______; affinity with 2,3-BPG less, and O2 moves from _________ Hb to _________.
2,3- BPG
O2
His-143; maternal; HbF
_________ = Globin alone.
__________= Heme + the globin chain.
Apoprotein
Holoprotein
Abnormal Oxidation of Heme Iron Pathway
(Fe+3) —> HEMICHROMES —> HEINZ BODIES
—-> RBC LYSIS——> Reticulocytes ↑, Bilrubin↑ (Jaundice), Hematocrit ↓
- Heme composed of __________ IX ring and _______ion
- Fe++ ion coordinated by 4_________atoms of ring, a proximal ______ residue and an ________molecule (in oxy-hemoglobin); 6th position empty in _________.
- ________ histidine H-bonds to the bound O2
Protoporphyrin; Fe2+
Nitrogen; histidine; O2; deoxyHb
Distal
Normal Adult Hemoglobin
- Each subunit adopts ________ fold; has no______; has ______ heme prosthetic group buried in crevice within subunit.
- The only charged residues in interior are histidine ______and ________, which bind_________or ________.
- __________ contacts between unlike subunits (ab) strongest: dimer of dimers
- Two a and two b subunits; a and b similar but not ______
- ________protein; inhibited by ___, _____, ______, ______, which lower __________affinity
Globin; B-sheets; one
E-7; F8; O2; Fe2+
Dimeric
Identical
Allosteric; H+; CO2; 2,3 BPG; Cl-; oxygen
Causes of Hypoxia: ________
Pre pulmonary (bronchitis)
Which is more strongly inhibited by 2,3BPG, adult or fetal hemoglobin?
Adult
Which version of iron is nonfunctional in hemoglobin?
Fe3+
The flow of oxygen
O2 —> Bronchi —> Lungs —> Hemoglobin —> (Myoglobin) —-> Mitochondria —> H2O
What problems can the sickle shape of cells cause?
The inability of RBC to fit through small capillaries
Aged RBC are taken up by _______ in the _______ and excreted in _______, during the process ______ are also released.
Phagocytes; spleen; bile; amino acids
Effect of CO
Binds to some ______ sites. Remaining “open” sites are shifted toward _______affinity
O2; higher
___________result from diminished production of a or b chains. Leads to unstable forms of ______ that are not fully functional and have low __________
Thalasssemias; Hb; solubility
Increase in hemocrit process
Renal pO2 decreases, which causes and increases in the Hypoxia inducible factor (HIF-1). Erythropoietin increases and then hemocrit increases.
Heme and Hemoglobin synthesis
Glcyine +Succinyl Co A—> 4 Pyrroles—-> Porphyrins + Fe2+—-> Heme + Globin Chains (alpha or beta)—-> Hemoglobin
Adult Blood: 96.8 % __________
- 7 % __________
- 47 % ___________
Fetal Blood: 90 % ___________
HbA1 (a 2b 2)
HbA2 (a 2d 2)
HbF (a 2g 2)
HbF
In “pure Hb,” _____-state highly unstable; ______-state favored
T; R
In beta hemoglobin types, the first amino acid is ______ and the last amino acid is _______
Valine; histidine
____________________________________________________________________
FORM OXID. 5TH COORD. 6TH COORD.
STATE
___________________________________________________________
DeoxyHb ___ His-F8 _______
OxyHb ___ His-F8 ________
Carbo-
monoxy Hb1 ___ His-F8 _______
Met Hb1 ____ His-F8 _______
Cyano Met
Hb 1 * _____ His-F8 ________
2+; Empty
2+; O2
2+; CO
3+; CN-, H2O, Cl-
3+; CN-
Aged red blood cells are taken up by the _________
Spleen
The _________ is the measure of degree of cooperative interaction between oxygen binding sites.
Hill coeffecient (nH)
A capillary is ________micrometers, but the RBC is _________ micrometers. The normal lifetime of a RBC
is ___________ days.
2-3; 8; 120
In alpha hemoglobin tyoes, the first amino acid is ______ and the last amino acid is _______
Valine; arginine
____ binding changes position of _____ Ion, which causes a global _________ change.
O2; Fe2+
Major hemoglobins in fetal stage
Alpha and gamma
Aged red blood cells are excreted in ___________
Bile
Total oxygen content
O2 on Hb (SaO2) + dissolved O2 (PO2 )
Hemoglobin hues:
________ - Healthy and robust
________ - Anemic
_______ - Hypoxemia - Cyanosis
_________ - Jaundiced (Bilirubin↑)
_________ - CO poisoning
_________ - Methemoglobinemia (Chocolate cyanosis)
Red
Pale
Blue
Yellow
Cherry Red
Brown Blue
What is hemocrit?
the ratio of the volume of red blood cells to the total volume of blood.
2,3-BPG is an __________ inhibitor
Allosteric
Bohr Effect
______ acidity gives more oxygen delivery
3 amino acid residues form 2________ bridges that stabilize the_______structure of deoxy-Hb
Addition of a proton to _________ is required
Protonation also occurs on ________ of a chains and ________ of a chains
Higher
Salt; T
His B 146
Amino-termini; His- 122
Anion transporter involved in O2-binding to hemoglobin. Symyporter or antiporter?
HCO3– Cl- antiporter
Chloride Effect
Cl- likewise promotes formation of _______
Cl- interacts with________ side chains of deoxy Hb and stabilizes ______ interactions
T-state
Positive; Ionic