18. Biochemistry | Globular Proteins

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68 Terms

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Structure Level of Myoglobin?

Tertiary (single polypeptide)

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Structure Level of Hemoglobin?

Quaternary (tetramer: 4 polypeptides)

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Subunits of Myoglobin?

1 α-helical chain (8 helices: A-H)

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Subunits of Hemoglobin?

2 α-chains + 2 β-chains (HbA); variants include δ or γ chains

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Heme Content of Myoglobin?

1 heme (porphyrin ring + Fe2+)

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Heme Content of Hemoglobin?

4 hemes (one per subunit)

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Histidine Coordination of Myoglobin?

Proximal His binds Fe2+; Distal His stabilizes O2

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Histidine Coordination of Hemoglobin?

Same as myoglobin for each subunit

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Location of Myoglobin?

Muscle cells

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Location of Hemoglobin?

Red blood cells (systemic circulation)

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Function of Myoglobin?

Stores O2; delivers to mitochondria (ETC Complex IV)

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Function of Hemoglobin?

Transports O2 and CO2 between lungs and tissues

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Variants of Hemoglobin?

HbA (Adult): α₂β₂ – ~95–98%; HbA₂ (Adult): α₂δ₂ – ~2–3%; HbF (Fetal): α₂γ₂ – higher O₂ affinity due to poor 2,3-BPG binding

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Binding Curve of Myoglobin?

Hyperbolic (non-cooperative)

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Binding Curve of Hemoglobin?

Sigmoidal (positive cooperativity)

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Hill Coefficient of Myoglobin?

1 (non-cooperative)

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Hill Coefficient of Hemoglobin?

~3 (cooperative)

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O2 Affinity of Myoglobin?

High at all pO2

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O2 Affinity of Hemoglobin?

Varies with pO2 due to T ⇄ R transition

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Role of Myoglobin?

Extracts O2 from Hb and delivers to mitochondria

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Role of Hemoglobin?

Delivers O2 from lungs to tissues

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Conformations of Hemoglobin?

T (Taut) = low O2 affinity; R (Relaxed) = high O2 affinity

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Trigger for T → R transition of Hemoglobin?

Movement of Fe2+ into the heme plane upon O2 binding

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Describe the T (Taut) state of hemoglobin.

Low O2 affinity, deoxygenated, favors O2 release

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Describe the R (Relaxed) state of hemoglobin.

High O2 affinity, oxygenated, favors O2 binding

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Mnemonic for T vs. R states?

T = Tense, Taut, Tissue, Tired; R = Relaxed, Ready, Respiration, Rich in O2

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What is the Bohr Effect?

↑ CO₂ or ↓ pH = reduced Hb affinity for O2

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Which histidine mediates the Bohr effect?

C-terminal His; protonation interacts with Asp-94→ favors T form

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Effect of ↑ [H⁺] (↓ pH, acidosis) on Hb O2 binding?

Decreases affinity→ Right shift (Bohr Effect's favors O2 release, T state)

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Effect of ↑ CO₂ + transported as bicarbonate HCO3- in blood on Hb O2 binding?

Decreases affinity→ Right shift (Forms carbaminohemoglobin, stabilizes T form)

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Effect of CO2 in lungs?

R form ↑ T form ↓

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Effect of ↑ 2,3-BPG on Hb O2 binding?

Decreases affinity→ Right shift (Binds between β-chains, promotes O2 unloading s/p T form

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Effect of ↑ Temperature on Hb O2 binding?

Decreases affinity→ Right shift (Enhances tissue O2 delivery)

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Effect of ↓ [H⁺] (↑ pH, alkalosis) i.e. in lungs on Hb O2 binding?

Increases affinity→ Left shift (Favors R state in lungs)

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Effect of CO on Hb O2 binding?

Artificially increases affinity→ Left shift (Prevents O2 release; loss of cooperativity)

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Effect of HbF on Hb O2 binding?

Increases affinity→ Left shift (γ-chains do not bind 2,3-BPG→ better maternal O2 uptake)

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CO Poisoning's Molecular Basis?

CO binds Hb 240x tighter than O2→ carboxyhemoglobin

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CO Poisoning's Clinical Features?

Hypoxia, dizziness, seizures, lactic acidosis, death

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CO Poisoning's Treatment?

100% O2 or hyperbaric O2

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Sickle Cell Disease's Molecular Basis?

β-chain mutation Glu6Val (E6V)→ hydrophobic HbS aggregates → sickled RBCs

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Sickle Cell Disease's Clinical Features?

Anemia, vaso-occlusive crises, pain in extremities

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Sickle Cell Disease's Treatment?

Hydroxyurea (↑ HbF), supportive

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Hemoglobin C Disease's Molecular Basis?

β-chain mutation Glu6Lys (E6K)

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Hemoglobin C Disease's Clinical Features?

Mild hemolytic anemia

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Hemoglobin C Disease's Treatment?

Supportive

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Hb Hammersmith's Molecular Basis?

Phe42Ser (F42S)→ destabilizes heme pocket→ heme loss

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Hb Hammersmith's Clinical Features?

Hemolytic anemia

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Hb Savannah's Molecular Basis?

Gly24Val (G24V)→ helix disruption→ unstable structure

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Hb Savannah's Clinical Features?

Hemolytic anemia

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Hb Milwaukee's Molecular Basis?

Val67Glu (V67E)→ Fe2+ oxidized to Fe2+ (methemoglobin)

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Hb Milwaukee's Clinical Features?

Cyanosis, chocolate-colored blood

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Methemoglobinemia's Molecular Basis?

Fe3+ Hb accumulation; NADH-methemoglobin reductase deficiency

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Methemoglobinemia's Clinical Features?

Cyanosis ('Blue People of Kentucky')

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Methemoglobinemia's Treatment?

Methylene blue

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α-Thalassemia's Molecular Basis?

Deletion of 1-4 α-globin genes (Chr 16)

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α-Thalassemia's Severity?

(Deletion of) 1 (a-globin gene): Silent; 2: Trait; 3: HbH disease; 4: Hb Bart (fatal)

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α-Thalassemia's Treatment?

Supportive

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β-Thalassemia's Treatment?

Transfusions, chelation therapy

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β-Thalassemia's Molecular Basis?

Mutation/deletion of 1-2 β-globin genes (Chr 11)

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β-Thalassemia's Severity?

1: Minor (mild anemia); 2: Major (Cooley’s anemia)

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HbA1c's Definition?

Non-enzymatic glycation of HbA in hyperglycemia→ diabetes marker

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When does Hb bind O2?

At high O2 levels (lungs, O2 rich after breathing in)

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When does myoglobin bind O2?

At low O2 levels (muscle, O2 poor after use) to deliver O to mitochondria ETC’s Complex 4 (cytochrome oxidase)

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HbA1c's Treatment?

Glucose control

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HbA1c's Clinical Features?

Chronic elevated HbA1c → diabetes mellitus indicator

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A neonate is found to have higher oxygen affinity hemoglobin than his mother. Which of the following best explains this physiological adaptation?

A. Expression of β instead of γ chains in fetal hemoglobin
B. Lack of 2,3-BPG binding due to γ chains
C. Increased CO₂ binding to fetal hemoglobin
D. Presence of hydrophobic patches in fetal hemoglobin
E. Higher expression of α-thalassemia genes

B

HbF (α₂γ₂) has poor 2,3-BPG binding, which leads to higher O₂ affinity, allowing the fetus to extract O₂ from maternal blood.

  • A. Fetal Hb has γ chains, not β chains.

  • B. Correct—γ chains reduce 2,3-BPG binding → left shift.

  • C. CO₂ transport does not increase O₂ affinity.

  • D. Hydrophobic patches are seen in sickle cell HbS.

  • E. Thalassemias reduce functional Hb, not increase affinity.

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A 17-year-old male presents with severe anemia and a positive family history of blood disorders. Genetic testing reveals deletion of three α-globin genes. Which of the following is most likely present in his peripheral blood?

A. Carboxyhemoglobin
B. Hemoglobin S
C. Heinz bodies
D. Methemoglobin
E. HbA1c

C

3 α-gene deletions = HbH disease, which leads to β₄ tetramers forming Heinz bodies (precipitated Hb).

  • A. Carboxyhemoglobin is from CO poisoning, unrelated to thalassemia.

  • B. HbS is a β-chain point mutation (sickle cell).

  • C. Heinz bodies are characteristic of HbH disease.

  • D. Methemoglobin is Fe³⁺ Hb, unrelated to α-thalassemia.

  • E. HbA1c is a diabetes marker, not relevant here.

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A 32-year-old man is rescued from a house fire and arrives confused and short of breath. Pulse oximetry reads 98%, but arterial blood gas shows hypoxia. What is the most likely cause of this discrepancy?

A. High levels of 2,3-BPG
B. Increased CO₂ forming carbaminohemoglobin
C. Conversion of hemoglobin to methemoglobin
D. Formation of carboxyhemoglobin preventing O₂ release
E. Glycosylation of hemoglobin reducing O₂ affinity

D

Carboxyhemoglobin forms in CO poisoning, which prevents O₂ unloading, causes a left shift, and makes SpO₂ readings falsely high.

  • A. 2,3-BPG affects tissue delivery but not pulse ox discrepancy.

  • B. Carbaminohemoglobin forms with CO₂ but does not cause pulse ox artifact.

  • C. Methemoglobinemia would decrease SpO₂ readings.

  • E. HbA1c has no acute effect on O₂ delivery.