Bioooo

• Hemoglobin


  Protein found only in red blood cells that transports oxygen from the lungs to the tissues and carbon dioxide from the tissues to the lungs

  
• Structure of hemoglobin


  • Conjugated protein consisting of globin (specialized protein) tightly bound to 4 heme molecules
  • Globin is a protein with four peptide chains joined together by non-covalent bonds (tetramer)

  
• Types of hemoglobin


  • Hemoglobin A
  • Hemoglobin A2
  • Hemoglobin A1c
  • Fetal hemoglobin (HbF)

  
• Hemoglobin A


  Major hemoglobin in adults (97%), consists of 2 α-chains and 2 β-chains

  
• Hemoglobin A2


  Minor component of normal adult hemoglobin, consists of 2 α-chains and 2 δ-chains

  
• Hemoglobin A1c


  Glycated form of hemoglobin A, glucose residues attached to β-globin chains, increased in diabetes

  
• Fetal hemoglobin (HbF)


  Hemoglobin present in the fetus during intrauterine life, consists of 2 α-chains and 2 γ-chains

  
• Hemoglobin F accounts for about 1% of adult human hemoglobin

  
• Hemoglobinopathies


  Diseases caused by abnormal globin formation or insufficient synthesis of normal hemoglobin

  
• Sickle cell anemia (hemoglobin S disease)

  • Blood cells contain abnormal hemoglobin S, with glutamate replaced by valine in β-chain
  • HbS molecules aggregate to form fibers, deforming red cells into sickle shape
  • Sickling blocks blood flow in small capillaries, leading to hypoxia, pain and cell death
  • Hemolysis of red blood cells

  
• Hemoglobin C disease


  • Hemoglobin variant with lysine substituted for glutamate in β-chain, causes mild chronic hemolytic anemia

  
• Hemoglobin SC disease


  • Some β-globin chains have sickle cell mutation, others have HbC mutation
  • Hemoglobin levels tend to be higher than sickle cell anemia, symptoms less frequent and severe

  
• Methemoglobinemia


  Oxidation of heme iron in hemoglobin from Fe2+ to Fe3+, binds oxygen irreversibly and cannot transport it

  
• Thalassemias


  • Anemias with reduced synthesis of either alpha (α-thalassemia) or beta (β-thalassemia) globin chains
  • Caused by gene deletions
  • May be homozygous with severe anemia or heterozygous (thalassemia trait) with no symptoms

  
• β-Thalassemias


  • Decreased or absent β-globin chain synthesis, excess unpaired α-chains precipitate causing premature red cell death
  • Increase in HbA2 and HbF
  • β-thalassemia minor have mild symptoms, β-thalassemia major require regular blood transfusions

  
• α-Thalassemias


  • Decreased or absent α-globin chain synthesis, depending on number of defective genes
  • Silent carrier has 1 defective gene, α-thalassemia trait has 2 defective genes
  • Hemoglobin H disease has 3 defective genes, hydrops fetalis has all 4 genes defective

  
• Hemoglobin Constant Spring


  Variant with abnormally long α-globin chain, causes thalassemic phenotype due to unstable mRNA and protein

  
• Porphyrins


  Cyclic compounds formed by linking four pyrrole rings through methyne bridges, with various side chains
• Heme


  Complex of protoporphyrin III and ferrous iron (Fe2+), with iron held in the center by bonds to pyrrole nitrogen atoms

  
• Heme biosynthesis


  1. δ-Aminolevulinic acid formation in mitochondria

  2. Porphobilinogen formation in cytoplasm

  3. Uroporphyrinogen formation in cytosol

  4. Heme formation in mitochondria

  
• Regulation of heme synthesis


  • ALA synthase is the rate-controlling enzyme, inhibited by heme, glucose, steroids, and stimulated by drugs/insecticides
  • Ferrochelatase and ALA dehydratase are sensitive to inhibition by lead

  
• Porphyrias


  Rare, inherited disorders of heme biosynthesis
• Heme synthesis


  1. Coproporphyrinogen III oxidase decarboxylates two propionate side chains to vinyl groups, generating protoporphyrinogen IX

  2. Protoporphyrinogen IX is oxidized to protoporphyrin IX

  3. Ferrous iron (Fe2+) is incorporated into protoporphyrin IX by ferrochelatase (heme synthase)

  
• Regulation of heme synthesis


  • ALA synthase is the regulatory (rate-controlling step) enzyme
  • ALA synthase is inhibited by heme, glucose, steroids
  • ALA synthase is stimulated by insecticides, drugs like barbiturate, griseofulvin, and iron
  • Ferrochelatase and ALA dehydratase are sensitive to inhibition by lead

  
• Porphyrias


  Rare, inherited (or sometimes acquired) defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors

  
• Types of porphyrias


  • Chronic hepatic porphyria (porphyria cutanea tarda)
  • Acute hepatic porphyrias (ALA dehydratase–deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, variegate porphyria)
  • Erythropoietic porphyrias (congenital erythropoietic porphyria, erythropoietic protoporphyria)
• Treatment of porphyrias


  1. Intravenous injection of hemin and glucose

  2. Protection from sunlight

  3. Ingestion of β-carotene (provitamin A)

  4. Phlebotomy (removes porphyrins)

  
• The average life span of the red blood cells is 120 days
• Catabolism of heme


  1. Heme ring is catabolized by microsomal heme oxygenase enzymes, removing iron (Fe++) and cleaving the ring between pyrrole rings I and II to form biliverdin and carbon monoxide

  2. Biliverdin is reduced to bilirubin by biliverdin reductase

  
• Unconjugated bilirubin


  Bilirubin that is nonpolar and insoluble in plasma, so it binds to plasma albumin

  
• Uptake and conjugation of bilirubin by the liver

  1. Bilirubin dissociates from albumin and enters hepatocytes

  2. Bilirubin is conjugated with glucuronic acid by UDP-glucuronyl transferase to form bilirubin monoglucuronide and bilirubin diglucuronide

  
• Secretion of bilirubin into bile


  Bilirubin diglucuronide is actively transported into the bile canaliculi and then into the bile
• Formation of urobilin in the intestine

  1. Intestinal bacteria remove the glucuronides from bilirubin diglucuronide and reduce bilirubin to colorless urobilinogens

  2. Some urobilinogens are reabsorbed and re-excreted in the bile, forming the enterohepatic urobilinogens cycle
• Excretion of urobilinogens


  1. Most urobilinogens are oxidized to colored urobilin and excreted in stool

  2. Some urobilinogens are reabsorbed and excreted in urine, where they contribute to the yellow color
• Jaundice


  The yellow color of skin, nail beds, and sclerae caused by bilirubin deposition due to increased bilirubin levels in the blood (hyperbilirubinemia)
• Types of jaundice


  • Hemolytic (prehepatic)
  • Hepatocellular (hepatic)
  • Obstructive (post-hepatic)
• Neonatal "physiologic" hyperbilirubinemia


  A transient condition in newborn infants, especially premature, due to low levels of UDP-glucuronyl-transferase enzyme leading to increased unconjugated bilirubin and jaundice

  
• Kernicterus


  Brain damage caused by free unconjugated bilirubin passing the blood-brain barrier when bilirubin levels exceed the albumin binding capacity
• Treatment of neonatal hyperbilirubinemia


  Phototherapy to convert bilirubin to more polar, water-soluble photoisomers that can be excreted without conjugation