hgb metabolism

• Hemoglobin


  One of the most studied proteins in the body due to the ability to easily isolate it from red blood cells (RBCs)
• Hemoglobin comprises approximately 95% of the cytoplasmic content of RBCs
• Free (non-RBC) hemoglobin


  Generated from RBCs through hemolysis, has a short half-life outside of RBCs
• When free hemoglobin is released into the plasma, it is rapidly salvaged to preserve its iron and amino acid components; when salvage capacity is exceeded, it is excreted by the kidneys
• Concentration of hemoglobin within RBCs

  Approximately 34 g/dL
• Hemoglobin's molecular weight


  Approximately 64,000 Daltons
• Hemoglobin's main functions


  • Transport oxygen from the lungs to tissues
  • Transport carbon dioxide from the tissues to the lungs for exhalation
  • Contribute to acid-base balance by binding and releasing hydrogen ions
  • Transport nitric oxide, a regulator of vascular tone
• This chapter covers the structure, biosynthesis, ontogeny, regulation, and function of hemoglobin
• The chapter also discusses the formation, composition, and characteristics of several dyshemoglobins, namely, methemoglobin, carboxyhemoglobin, and sulfhemoglobin
• Heme


  Consists of a ring of carbon, hydrogen, and nitrogen atoms called protoporphyrin IX, with a central atom of divalent ferrous iron (Fe2+)
• Each of the four heme groups is positioned in a pocket of the polypeptide chain near the surface of the hemoglobin molecule
• The ferrous iron in each heme molecule reversibly combines with one oxygen molecule
• When the ferrous irons are oxidized to the ferric state (Fe3+), they no longer can bind oxygen
• Globin chains comprising each hemoglobin molecule

  • Alpha
  • Beta
  • Gamma A
  • Gamma G
  • Delta
  • Epsilon
  • Zeta
  • Theta
• Globin chain


  141 to 146 amino acids each
• Each globin chain is divided into eight helices separated by seven nonhelical segments
• Primary structure of hemoglobin

  Amino acid sequence of the polypeptide chains
• Secondary structure of hemoglobin

  Chain arrangements in helices and nonhelices
• Tertiary structure of hemoglobin


  Arrangement of the helices into a pretzel-like configuration
• Quaternary structure of hemoglobin


  The complete hemoglobin molecule, a spherical tetramer with four heme attached to four polypeptide chains
• The predominant adult hemoglobin, Hb A, is composed of two alpha-globin chains and two beta-globin chains
• A small percentage of Hb A is glycated, where glucose attaches to the N-terminal valine of the beta chain
• Normally, about 4% to 6% of Hb A circulates in the A1c form, but in uncontrolled diabetes mellitus, the amount of A1 is increased proportionally to the mean blood glucose level over the preceding 2 to 3 months
• Heme biosynthesis


  1. Begins in the mitochondria with the condensation of glycine and succinyl coenzyme A to form aminolevulinic acid (ALA)

  2. ALA undergoes several transformations in the cytoplasm to form coproporphyrinogen III

  3. In the mitochondria, protoporphyrinogen IX is converted to protoporphyrin IX

  4. Ferrous (Fe2+) ion is added, catalyzed by ferrochelatase to form heme
• Transferrin, a plasma protein, carries iron in the ferric (Fe3+) form to developing erythroid cells
• Globin biosynthesis


  1. Six structural genes code for six globin chains

  2. The alpha- and beta-globin genes are on the short arm of chromosome 16

  3. The epsilon-, gamma-, delta-, and beta-globin gene cluster is on the short arm of chromosome 11
• Heme production


  1. Glycine and succinyl CoA form ALA

  2. ALA synthase catalyzes

  3. Fe²+ combines with protoporphyrin IX

  4. Ferrochelatase (heme synthase) present
• Transferrin


  Plasma protein that carries iron in the ferric (Fe³+) form to developing erythroid cells
• Iron transport into erythroid cells

  1. Transferrin binds to transferrin receptors

  2. Receptors and transferrin brought into cell in endosome

  3. Acidification of endosome releases iron

  4. Iron transported out of endosome and into mitochondria

  5. Iron reduced to ferrous state

  6. Iron united with protoporphyrin IX to make heme
• Heme leaves the mitochondria and is joined to the globin chains in the cytoplasm
• Globin genes


  • 6 structural genes code for 6 globin chains
  • α- and β-globin genes on chromosome 16
  • ε-, γ-, δ-, and β-globin gene cluster on chromosome 11
• There is one copy of each globin gene per chromatid, for a total of two genes per diploid cell, with the exception of α and γ which have two copies per chromatid
• Globin chain production


  1. Transcription in nucleus

  2. Translation on ribosomes in cytoplasm

  3. Less efficient translation of α-globin mRNA
• Hemoglobin assembly


  1. Globin chains bind to heme

  2. Form heterodimers

  3. Two heterodimers combine to form tetramer
• Hemoglobin types


  Hb A: 2α and 2β chains

  Hb A₂: 2α and 2δ chains

  Hb F: 2α and 2γ chains
• Hb A₂ comprises less than 3.5% of total hemoglobin in adults
• In healthy adults, Hb F comprises 1% to 2% of total hemoglobin, and it is present only in a small proportion of the RBCs
• Hemoglobin ontogeny


  Hemoglobin composition changes with prenatal gestation time and postnatal age

  Reflects sequential activation and inactivation of globin genes
• Hemoglobin types during development

  • ζ- and ε-globin chains (embryonic hemoglobins)

  Hb F (α₂γ₂) (predominant during fetal life and at birth)

  Hb A (α₂β₂) (predominant from 6 months of age through adulthood)
• Heme regulation


  Heme inhibits transcription of ALA synthase gene

  Heme inhibits other enzymes in biosynthesis pathway

  Increased demand for heme induces increased ALA synthase synthesis