Chpt 7: Myoglobin Hemoglobin Flashcards
Myoglobin
- Heme protein present in heart and skeletal muscle
- function as reservoir and oxygen carrier
- bind one oxygen molecule per myoglobin (NOT cooperativity) HYPERBOLIC CURVE
Myoglobin has higher affinity for oxygen than Hemoglobin
Structure: Protein bound to Heme
Protein:
-150 amino acids, amino acids with non polar R groups on inside, amino acids with charged R groups on surface of molecule
-8 alpha helixes (A-H)
Oxygen Information
expressed in pO2
Barometric pressure-760 mmHg or 760 torr or 101.3 kPa or 1 atm
Atmosphere-150 to 160 mmHg Lung and Arterial Blood-100mmHg tissue: -resting-40mmHg -exercising-20mmHg
Heme
- structure
- function
Structure:
1) Protoporphyrin IX and ferrous (Fe2+)
- Ferrous Iron (Fe2+ or Iron II) bind Oxygen; Ferric Iron (Fe3+) will not bind Oxygen
2) Prosthetic group
- nonprotein factor, organic molecule (NADH, FADH) covalently attached enzyme (nondissociable)
- needed for enzyme activity
3) Iron forms 6 bonds
- Four with N of protoporphyrin
- one with proximal histidine (Helix F) of globin protein’
- one with oxygen stabilized by distal histidine (Helix E)
- as oxygen binds, iron moves into the plane of hemoglobin
Function:
- Binds/carries oxygen In hemoglobin and myoglobin
- carries electrons for redoxreactions-cytochrome
- breaks down hydrogen peroxide-catalase
Hemoglobin
- carries oxygen, CO2, and protons
- found exclusively in RBC
- exhibits cooperativity (sigmoidal curve);as one oxygen binds, the affinity for oxygen is increased
- Hemoglobins affinity for the fourth Oxygen is 300x that of the first oxygen
Structure: Heterotetramer -2 alpha chains -2 beta chains -subunits bind by hydrophobic interactions -each subunit binds one heme
Hemoglobin: T vs R form
T (tense or tau) form=deoxygenated form
- low affinity for oxgyen
- weak ionic and hydrogen bonds occur between AB dimer pairs
- Strong interactions primarily hydrophobic holding A and B chains together to form stable AB dimer
R (relaxed) Form=oxygenated form
- high affinity for oxygen
- some hydrophobic between AB dimers are broken in oxygenated form
Dissociation curve
steepest at the oxygen conc that occur in the tissue;
allows oxygen delivery to respond to small changes in pO2
Allosteric Effectors of Hemoglobin
1) pH (Bohr Effect)
- release of oxygen is enhanced by increase in H+ conc (or decrease in pH) which lowers the affinity of Hemoglobin for Oxygen
- pH in alveoli of lungs is higher (7.6)
- pH in tissue is lower (7.2) due to production of organic acids (lactate acid) and CO2
2) pCO2
- release of oxygen is enhanced by increased CO2 conc which lowers the affinity of hemoglobin for oxygen BEYOND pH EFFECT
- most is transported as carbonic acid/bicarbonate
- some CO2 bind to amino group hemoglobin forming carbamate
3) 2,3-Bisphosphoglycerate (2,3-BPG)
- synthesized from intermediate in glycolysis
- most organic phosphate in RBC
- release of oxygen is enhanced by increase in 2,3-BPG conc., because it binds to the pocket formed by the two beta chains (contains positively charged amino acids)
- stabilizes taut form of Hemoglobin
ALL SHIFT RIGHT
Transfused Blood
stripped of 2,3 BPG
- prevented by adding inosine
- enters hexose monophosphate pathway
Citrate is used when blood is transfused
Carbon Monoxide Poisoning
CO binds tightly but reversibly to iron of hemoglobin
-replaces oxygen
Traps Hemoglobin in relaxed from and oxygen is not released into tissue
-shift curve to hyperbola
Fetal Hemoglobin in pregnancy
Has higher affinity for oxygen than Adult hemoglobin (HbA) due to weak binding of 2,3 BPG which facilitates transfer of oxygen across placenta from mother to fetus
Alpha Globin Gene Family vs Beta Globin Gene Family
Alpha Globin Gene Family-Chromosome 16
- Zeta-two copies
- alpha-16p13.3-two copies
Beta Globin Gene Family-chromosome 11
- Epsilon
- Gamma types A and G
- Beta-11p15.4-single copy
types of hemoglobin
Embryonic Hemoglobin(HbE)-first 3 months of gestration
- Hb-Grower 1-Major type; 2 Zeta and two epsilon subunits
- Hb-Grower II-two alpha and two epsilon subunits
- Hb-Protland I-two zeta and two gamma subunits
- Hb-Portland II-two zeta and two beta subunits
Fetal Hemoglobin (HbF)
- final 6 months of gestation thru first few months after birth
- completelely replaced by adult hemoglobin by 6-12 months
- HbF-2 alpha and 2 beta subunits
Adult Hemoglobin (HbA)
- HbA-2 alpha and two beta subunits-95/98% of hemoglobin in adults
- HbAii- two alpha and two delta subunits 2 to 3% of hemoglobin in adults
- Fetal Hemoglobin-2 alpha and 2 gamma subunits can be found in small quantities in adults
Hemoglobinopathies
Sickle cell disease
- Hemoglobin S disease
- Sickle Cell anemia
Hemoglobin C disease
Hemoglobin SC disease
Methenoglobinemias
Thalassemias
Sickle Cell Disease (HbS)
- Type of disorder; Prevalence?
- cause
- increased risk for
- selective advantage?
- treatment
Autosomal Recessive disorder
- 1/500 newborn African American
a) homozygous=disease (1/500)
b) heterozygous=carrier (1/10)
Cause:
- Point mutation (SNP-single nucleotide polymorphism) in beta globin gene
a) GAG to GTG - Point mutation leads to single amino acid change in sixth position of hemoglobin beta protein glu to val
Hbs form fibers that distort erythrocyte; elongated erythrocytes occlude blood flow in capillaries which results in microinfarcts which produce tissue anoxia resulting in severe pain
Increase -suscepptiblilty to infections -acute chest syndrome stroke -splenic and renal dysfunction
Selective Advantage:
Plasmodium falciparum human parity obligatory part of life cycle in RBC
-the shorter life span of RBC’s in heterozygous individuals prevents P. falciparum from completing its life cycle thus. -heterozygotes are less susceptible to malaria
Treatments:
- adequate hydration and analgesics
- aggressive antibiotic therapy for infection
- transfusions
- Hydroxyurea-antitumor drug
Hemoglobin C disease
Point mutation in beta globin gene
-lead to single amino acid change in sixth position (new 7th) of hemoglobin beta protein glu to lys
Homozygous individuals have a mild, chronic hemolytic anemia
-no infarctive crisises and no treatment necessary
