Week 5: Biochemistry and Physiology of Hemoglobin and Myoglobin

Vocabulary practice flashcards covering the structure, ligand binding kinetics, allosteric regulation, genetics, and pathologies of myoglobin and hemoglobin.

Hemoglobin

The most abundant protein in red blood cells that transports oxygen from the lungs to tissues and aids in the transport of carbon dioxide and hydrogen ions back to the lungs.

Myoglobin

A monomeric oxygen-binding protein located in muscle tissue that provides a reserve supply of oxygen during times of need.

Heme

The prosthetic group of hemoglobin and myoglobin consisting of a protoporphyrin organic ring bound to a single iron atom in its ferrous ($\text{Fe}^{2+}$) state.

Ferrous iron ($\text{Fe}^{2+}$)

The reduced oxidation state of iron that is capable of binding oxygen; iron in the ferric ($\text{Fe}^{3+}$) state cannot bind oxygen.

Proximal histidine

The histidine residue designated as His F8 whose imidazole ring occupies the 5th coordination site of the heme iron atom.

Distal histidine

The histidine residue designated as His E7 located on the side of the heme plane where oxygen binds, forming a hydrogen bond to bound molecular oxygen.

6th coordination site

The binding position on the heme iron atom opposite the proximal histidine where molecular oxygen ($O_2$) binds reversibly.

Functional magnetic resonance imaging (fMRI)

A brain-imaging method that relies on alterations in the magnetic properties of hemoglobin when oxygen binds to the heme iron.

Association constant ($K_a$)

The equilibrium constant describing reversible protein-ligand binding, expressed by the equation $K_a = \frac{[PL]}{[P][L]}$.

Dissociation constant ($K_d$)

The reciprocal of the association constant ($K_d = \frac{1}{K_a}$) representing the ligand concentration at which half ($50\%$) of all available binding sites are occupied.

Fractional saturation ($\theta$)

The fraction of total ligand-binding sites on a protein occupied by ligand, calculated as $\theta = \frac{[PL]}{[PL] + [P]} = \frac{[L]}{[L] + K_d}$.

$$P_{50}$$

The partial pressure of oxygen at which a protein is half-saturated ($\theta = 0.5$); it is $2\,\text{torr}$ for myoglobin and $26\,\text{torr}$ for normal adult hemoglobin.

Cooperativity

A binding mechanism in multimeric proteins where oxygen binding at one heme site increases the likelihood of oxygen binding to the remaining unoccupied sites within the tetramer.

Allosteric protein

A protein in which ligand binding at one specific site alters the binding properties and affinity at a different site on the same protein.

T state

The tense conformation of hemoglobin characterized by lower oxygen affinity, which is the predominant structural state of deoxyhemoglobin.

R state

The relaxed conformation of hemoglobin characterized by significantly higher oxygen affinity, which is the predominant structural state of oxyhemoglobin.

Carboxyhemoglobin (COHb)

The complex formed when carbon monoxide (CO) binds to hemoglobin at the oxygen-binding site with an affinity $200$ times tighter than oxygen.

Bohr effect

The physiological effect described by Christian Bohr in 1904 wherein low pH (increased $H^+$) and elevated $CO_2$ reduce hemoglobin's affinity for oxygen, promoting oxygen unloading.

Carbamate

A negatively charged group produced when $CO_2$ reacts with terminal amino groups of hemoglobin subunits, forming salt bridges at the $\alpha\beta$ dimer interface that stabilize the T state.

2,3-Bisphosphoglycerate (2,3-BPG)

An allosteric regulator found in erythrocytes that binds the central cavity of hemoglobin to stabilize the T state and reduce oxygen affinity.

Fetal hemoglobin (HbF)

A hemoglobin tetramer comprising two $\alpha$ chains and two $\gamma$ chains ($\alpha_2\gamma_2$) that has a higher oxygen affinity than maternal adult hemoglobin due to decreased 2,3-BPG binding.

H143S substitution

The amino acid change in the $\gamma$ chain of fetal hemoglobin where serine replaces histidine at residue 143, removing a positive charge from the 2,3-BPG-binding site.

Hb Gower 1

An embryonic hemoglobin composed of two zeta chains and two epsilon chains ($\zeta_2\epsilon_2$) with a $P_{50}$ of $4\,\text{mmHg}$ and a Hill coefficient of $1.9$.

Hb Gower 2

An embryonic hemoglobin composed of two alpha chains and two epsilon chains ($\alpha_2\epsilon_2$) with a $P_{50}$ of $12\,\text{mmHg}$ and a Hill coefficient of $2.4$.

Hb Portland 1

An embryonic hemoglobin composed of two zeta chains and two gamma chains ($\zeta_2\gamma_2$) with a $P_{50}$ of $6\,\text{mmHg}$ and a Hill coefficient of $2.3$.

HbA2

A minor form of adult hemoglobin composed of two alpha chains and two delta chains ($\alpha_2\delta_2$).

Sickle-cell anemia

An autosomal recessive hemoglobinopathy resulting from the aggregation of mutated deoxyhemoglobin molecules into insoluble fibres.

E6V mutation

The specific substitution identified by Vernon Ingram in 1956 where glutamic acid is replaced by valine at position 6 of the $\beta$ globin chain, creating a hydrophobic patch that initiates sickle hemoglobin aggregation.

$\alpha$-Thalassemia

An autosomal recessive condition caused by deficient or absent $\alpha$-globin synthesis, resulting in tetramers of $\beta$-subunits only that bind oxygen with high affinity and no cooperativity.

$\beta$-Thalassemia

An autosomal recessive disorder caused by the loss or reduction of $\beta$-globin synthesis, leading unpartnered $\alpha$ chains to form insoluble aggregates that destroy red blood cells.

Thalassemia major

The most severe clinical form of $\beta$-thalassemia, also referred to as Cooley anemia or Mediterranean anemia.