Hemoglobin

Hemoglobin

Structure of Hemoglobin

  • Molecular Structure:

    • Composed of heme group attached to globin chains.

    • Contains iron atom within the heme group responsible for oxygen binding.

    • Each hemoglobin can bind four oxygen molecules.

Hemoglobin Function

  • Oxygen Transport:

    • Hemoglobin carries oxygen via loose and reversible binding to iron in heme.

  • Conformational States:

    • Tense State (T): Deoxygenated hemoglobin.

    • Relaxed State (R): Oxygenated hemoglobin.

    • Oxygen binding to T-state promotes a structural change enhancing oxygen binding (cooperative binding).

Hemoglobin Dissociation Curve

  • P50 Value:

    • Represents the partial pressure of oxygen at which hemoglobin is 50% saturated. Higher P50 = lower affinity for oxygen.

    • Factors stabilizing the deoxy (T-state) decrease affinity, shifting the curve right.

Factors Shifting the Curve to the Right

  • Increased levels of:

    • pCO2

    • H+ protons (lower pH)

    • Temperature

    • 2,3-BPG (2,3-diphosphoglycerate)

    • Conditions of chronic hypoxia.

Bohr Effect

  • Mechanism:

    • Increased hydrogen ions bind to hemoglobin's amino acids, stabilizing T-state and decreasing oxygen affinity.

    • Resulting decrease in pH promotes oxygen unloading in tissues.

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

  • Function:

    • Produced in RBCs in response to hypoxia or high altitude.

    • Binds to hemoglobin, stabilizing T-state and further reducing oxygen affinity.

Exercise Impact on Hemoglobin

  • Example:

    • During intense exercise (e.g., running), excess protons stabilize R state, increasing P50 and shifting the oxygen binding curve left, enhancing oxygen delivery.

Heme Synthesis

  • Chemical Pathway:

    • Initiated by Glycine + Succinyl-CoA → Aminolevulinic acid (ALA) → Porphobilinogen → Hydroxymethylbilane → Uroporphyrinogen III → Protoporphyrinogen IX → Coproporphyrinogen III → Protoporphyrin IX → Heme

    • Occurs in the mitochondria and cytoplasm.

Sideroblastic Anemia

  • Causes:

    • Associated with ALA synthase deficiency, Vitamin B6 deficiency and substances like lead poisoning, which inhibit ALA dehydratase and ferrochelatase.

    • Ineffective heme synthesis leads to iron accumulation in mitochondria, causing sideroblast formation.

Porphyrias

  • Types:

    • Acute Intermittent Porphyria: Caused by porphobilinogen deaminase deficiency; patient experiences acute abdominal pain, seizures, psychiatric symptoms, and port-wine urine.

    • Porphyria Cutanea Tarda: Caused by uroporphyrinogen decarboxylase deficiency; manifests as blistering photosensitivity.

Hemoglobin Composition

  • Chain Variants:

    • Fetal Hemoglobin (HbF): Composed of two alpha and two gamma chains, produced in utero and first six months post-birth.

    • Adult Hemoglobin (HbA): Made of two alpha and two beta chains, forms majority in adults (95%).

    • HbA2: Composed of two alpha and two delta chains.

Thalassemia Overview

  • Alpha Thalassemia:

    • Result from mutations in alpha globin genes which affect the balance of globin chains.

    • Excess beta chains lead to formation of Hemoglobin H (HbH) and, in extreme cases, Hemoglobin Bart’s which have high oxygen affinity but poor tissue delivery.

  • Beta Thalassemia:

    • Mutations in beta chains lead to excess unpaired alpha chains forming unstable polymers, causing ineffective erythropoiesis and hemolysis.

  • Clinical Manifestations:

    • Beta-thalassemia trait presents as asymptomatic anemia, while major leads to severe anemia early in life, manifesting as failure to thrive and splenomegaly.

    • Diagnostic insights gained through hemoglobin electrophoresis reveal characteristic patterns.

Sickle Cell Anemia

  • Genetic Mutation:

    • Point mutation in beta-globin chain causes hydrophobic valine replacement of glutamate, leading to polymerization of deoxygenated HbS and sickling of RBCs.

  • Clinical Implications:

    • Microvascular occlusion risk increasing with factors like low pH, increased pCO2, or dehydration, leading to pain crises and acute chest syndrome.

Hemoglobin Metabolism

  • Lifecycle of RBC:

    • Old RBCs are phagocytosed in spleen/liver leading to iron salvage into ferritin.

    • Heme is degraded into biliverdin and bilirubin; bilirubin transported to liver for conjugation and elimination into bile.

Questions?

  • Open for discussion regarding the presented topics on hemoglobin and related pathophysiology.