Myoglobin and Hemoglobin: Structure, Function, and Oxygen Binding
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218 Terms
Myoglobin
What protein stores oxygen in muscle?
153 amino acids in a single polypeptide chain
How many residues are in myoglobin?
Monomeric
Is myoglobin a monomer or multimer?
No, because it has only one subunit and one oxygen-binding site
Can myoglobin exhibit cooperativity?
All-alpha globin fold
What type of protein fold does myoglobin have?
A tightly packed hydrophobic core
What makes the interior of myoglobin have almost no empty space?
Oxygen storage in muscle
What is the primary function of myoglobin?
A non-protein unit permanently bound to a protein and required for its function
What is a prosthetic group?
The protein without its prosthetic group
What is an apoprotein?
The complete functional protein including its prosthetic group
What is a holoprotein?
Six
How many coordination positions does heme iron have?
It donates a hydrogen bond that stabilizes bound oxygen
How does the distal histidine stabilize oxygen?
It forces carbon monoxide to bind at an angle
How does the distal histidine reduce carbon monoxide binding?
About 20,000 times more tightly
How much more tightly does free heme bind CO than O2?
About 200 times more tightly
How much more tightly does globin-bound heme bind CO than O2?
Fe2
+ Which oxidation state of iron binds oxygen reversibly?
Fe3
+ Which oxidation state of iron cannot bind oxygen?
Methemoglobin
What results when heme iron becomes permanently oxidized to Fe3+?
About 0.4 Å below the porphyrin plane
Where does iron sit in deoxyhemoglobin?
About 0.4 Å
How far does iron move when oxygen binds?
It becomes six-coordinate and moves into the plane of the porphyrin ring
What happens to iron when oxygen binds?
It has no second subunit to transmit the movement to
Why does iron movement not produce cooperativity in myoglobin?
Allostery
What is the term for an effect at one site caused by an event at a different site?
Alpha2beta2
What is the quaternary structure of adult hemoglobin HbA?
Four
How many subunits does hemoglobin contain?
Two alpha chains of 141 residues and two beta chains of 146 residues
What are the subunits and chain lengths of hemoglobin?
Four
How many heme groups does hemoglobin contain?
Four
How many oxygen molecules can one hemoglobin tetramer bind?
The globin fold
What protein fold does each hemoglobin subunit adopt?
Cooperativity
What property allows binding at one heme to raise affinity at the other sites?
Hyperbolic
What is the shape of the myoglobin oxygen-binding curve?
Sigmoidal
What is the shape of the hemoglobin oxygen-binding curve?
1.0
What is the Hill coefficient of myoglobin?
About 2.8
What is the approximate Hill coefficient of hemoglobin?
Store oxygen in muscle
What is the primary job of myoglobin?
Load oxygen in the lungs and unload it in tissues
What is the primary oxygen-related job of hemoglobin?
T state
Which hemoglobin state is tense and deoxygenated?
R state
Which hemoglobin state is relaxed and oxygenated?
A network of ion pairs and hydrogen bonds
What stabilizes the T state?
Wide open
What happens to the central cavity in the T state?
Low
What is the oxygen affinity of the T state?
The central cavity
Where does 2,3-BPG bind in hemoglobin?
They break
What happens to salt bridges during the transition to the R state?
It narrows and closes
What happens to the central cavity in the R state?
High
What is the oxygen affinity of the R state?
It is expelled
What happens to 2,3-BPG when hemoglobin transitions to the R state?
Right shift
What happens to the oxygen dissociation curve when the T state is stabilized?
Left shift
What happens to the oxygen dissociation curve when the R state is stabilized?
It lacks neighboring subunits
What does myoglobin physically lack that prevents cooperativity?
Higher P50
What happens to P50 during a right shift?
Lower oxygen affinity
What happens to hemoglobin oxygen affinity during a right shift?
Easier oxygen unloading
What happens to oxygen delivery during a right shift?
Lower P50
What happens to P50 during a left shift?
Higher oxygen affinity
What happens to hemoglobin oxygen affinity during a left shift?
Tighter oxygen holding
What happens to oxygen release during a left shift?
Cooperativity
What property is measured by the Hill coefficient?
No cooperativity
What does an nH of 1 mean?
Increased H or decreased pH
What pH-related change causes a right shift of the oxygen dissociation curve?
The Bohr effect
What is the name for the effect of increased H+ or decreased pH on hemoglobin oxygen affinity?
Increased CO2
What gas causes a right shift by forming carbamates and generating H+?
Carbamate formation on N-terminal alpha-amino groups
How does CO2 directly stabilize the T state?
Increased 2,3-BPG
What glycolytic intermediate shifts the oxygen dissociation curve to the right?
Chronic hypoxia, anemia, and altitude
When do red cells increase 2,3-BPG?
Hot, acidic, and CO2-rich
What conditions characterize a hard-working tissue and promote oxygen release?
Fetal hemoglobin HbF
Which form of hemoglobin has a left-shifted oxygen dissociation curve compared with HbA?
Alpha2gamma2
What is the subunit composition of fetal hemoglobin?
Serine
Which amino acid replaces His143 in the gamma chain of HbF?
2,3-BPG binds weakly
Why does fetal hemoglobin have a higher oxygen affinity?
T state
What hemoglobin state does 2,3-BPG stabilize?
R state
Which hemoglobin state is strongly favored when 2,3-BPG is absent?
About 8%
Approximately what percentage of oxygen would hemoglobin stripped of 2,3-BPG release between lung and tissue?
About 66%
Approximately what percentage of oxygen do real red cells release between lung and tissue according to the lecture?
An allosteric inhibitor
How is 2,3-BPG classified?
It binds away from the heme and lowers oxygen affinity
Why is 2,3-BPG considered an allosteric inhibitor?
Lower affinity of HbF for 2,3-BPG
What allows oxygen transfer from maternal blood to fetal blood across the membrane
Wrong protein versus not enough protein
What is the major distinction between a structural hemoglobin variant and thalassemia?
A missense substitution changing one amino acid residue
What typically causes a structural hemoglobin variant?
Glu6 to Val in the beta chain
What mutation causes sickle hemoglobin HbS?
Glu6 to Lys in the beta chain
What mutation causes hemoglobin C HbC?
Not enough normal globin protein is synthesized
What is thalassemia?
Reduced or absent synthesis of a globin chain
What is the underlying defect in thalassemia?
Gene deletions
What is the usual cause of alpha-thalassemia?
Point mutations affecting promoter, splicing, or translation
What is the usual cause of beta-thalassemia?
Fetal life
When does alpha-thalassemia become clinically relevant?
After about six months of age
When does beta-thalassemia typically become clinically apparent?
Beta chains appear mainly after birth as HbF is replaced by HbA
Why is beta-thalassemia usually silent at birth?
A hydrophobic patch
What surface change does the Glu6-to-Val substitution create in HbS?
It becomes rigid and distorted into a sickle shape and may eventually lyse
What happens to red cells after HbS polymerization?
HbSS
What genotype is associated with sickle cell disease?
HbAS
What genotype is associated with sickle cell trait?
Avoid low oxygen tension
What is the major dental management principle for patients with sickle cell disease?
Pulpal necrosis in intact, uncarious teeth
What unusual dental finding can result from infarction of the pulpal microcirculation in sickle cell disease?
HbF, HbA, and HbS
What does an FAS newborn screening pattern indicate?
Sickle cell trait
What diagnosis is associated with an FAS newborn screening pattern?
HbF and HbS with no HbA
What does an FS newborn screening pattern indicate?
Sickle cell disease
What diagnosis is associated with an FS newborn screening pattern?
Fe2 to Fe3+
+ What oxidation change occurs in methemoglobinemia?
Ferric iron cannot bind oxygen
Why does methemoglobin reduce oxygen carriage?
Less oxygen is carried and the oxygen that is carried is released less readily
Why does oxygen delivery fall twice over in methemoglobinemia?
Amphipathic
What property of phospholipids allows them to form bilayers?