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Hemoglobin and hemoglobinpathies. Srbová Martina Kotaška Karel. Hemoproteins . Consist of hem cyclic tetrapyrrole 1 iron cation Fe 2+ bound in the middle of tetrapyrrole skelet by coordination coavalent bonds conjugated system of double bonds. methine bridge. pyrrole ring.

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hemoglobin and hemoglobinpathies

Hemoglobin and hemoglobinpathies

Srbová Martina

Kotaška Karel


Consist of hem

  • cyclic tetrapyrrole
  • 1 iron cation Fe2+ bound in the middle of tetrapyrrole skelet by coordination coavalent bonds
  • conjugated system of double bonds

methine bridge

pyrrole ring

types of hemoglobin
Types of hemoglobin

Adult HbA1: 2α and 2β subunits (98%HbA)

Adult HbA2: 2α and 2δ subunits (2% HbA)

Fetal HbF: 2α and 2γ

have higher O2 affinity than HbA – take up oxygen from the maternal circulation

Embryoinic: 2and 2

2 and 2 

2 and 2

have higher O2 affinity than HbA


Hemoglobin switching

Alteration of globin gene expresion during development


Redox state Fe 2+

  • Hemoglobin (transports O2 to the tissues)
  • Myoglobin (stores O2 in the muscles)
  • Cytochromes (e- carriers in ETC)
  • Catalase + peroxidases (decomposition of peroxides)
  • Cytochrome P-450 (hydroxylation)
  • Desaturasases FA (desaturation FA)

Redox state Fe 2+ Fe 3+

structure of hemoglobin
Structure of Hemoglobin
  • 4 polypetide subunits (globins)
    • Hb A (adults) heterotetramer 2α a 2β
    • Each subunit contains 1 hem group
    • 8 helices (A-H) β subunit
    • 7 helices α subunit
    • Hydrofobic pocket

- protect hem against oxidation

structure of hemoglobin1
Structure of Hemoglobin
  • Hem binding to globin
    • Fe 2+ is coordinated by N atom from proximal histidin F8
  • Binding of O2
    • distal histidin E7 hydrogen bonds to the O2

Structureof Hemoglobin

  • Quaternary structure

Interactions between subunits

1) hydrofobic ( between α-β)

2) electrostatic (between α-α; β-β, α-β)

        • O2 binding – loss of these interactions





structure of myoglobin
Structure of Myoglobin
  • 1 polypeptide chain (153 AA)
  • 1 hem
  • Tertiary structures of the α and β subunits are remarkably similar, both to each other and to that of Mb
  • Skeletal and heart muscles
binding of o 2 oxygenation
Binding of O2 (oxygenation)
  • Oxygenation changes the electronic state of the Fe2+ - hem
  • Color change of blood from dark purplish (venous) to the brilliant scarlet color (arterial)
mechanism of oxygen binding cooperativity
Mechanismof oxygen-bindingcooperativity
  • The binding of the first O2 to Hb enhances the binding futher O2 molecules
  • O2 affinity of Hb increases with increasing pO2
  • Sigmoidal saturation curve
  • Hyperbolic curve for Mb - no cooperative behavior

Saturation O2

  • Hb loads O2 to about 90% saturation under the arterial partial pressure
  • Hb travels to the tissue where the O2 partial pressure is 20 torr, most of Hb´s bound O2 is released

The diference in oxygen affinity between Mb and Hb is greatest between 5 and 30 torr, where Mb binds much more O2 than does Hb. This difference allows O2 to be released at the tissues from O2 - loaded Hb, and transported to Mb

Saturation O2


The loss of electrostatic interactions induce

  • conformational changes in all other subunits
  • The movement of Fe 2+ into the heme plane triggers the T→R conformational shift
conversion of t form r form
Conversion of T form→R form

T form (tense)

R form (relaxed)

The binding of the first O2 molecule to subunit of the T-form leads to a local conformational change that weakens association between the subunits  R-form

allosteric effectors
Allosteric effectors

Influence the equilibrium between T and R forms

  • CO2
  • H+
  • 2,3-bisphosphoglycerate

Decrease O2 affinity of Hb

2 3 bisphosphoglycerate
2,3 - bisphosphoglycerate
  • binds selectively to deoxy-Hb
  • stabilizes T form
  • lowers the affinity of Hb for oxygen
  • oxygen is more readily released in tissues
2 3 bisphosphoglycerate1
2,3 - bisphosphoglycerate

Clinical aspects:

  • In people with high-altitude adaptation or smokers the concentration of 2,3-BPG in the blood is increased  increases the amount of oxygen that Hb unloads in the capilaries
  • Fetal hemoglobin (HbF α2γ2), has low BPG affinity – the higher O2 affinity – facilitates the transfer of O2 to the fetus via the placenta
bohr effect
Bohr effect
  • The binding of protons H+ by Hb lowers its affinity for O2
  • Increasing pH, that is, removing protons,stimulates Hb to bind O2
  • pH of the blood decreases as it enters

tissues because CO2 produced by

metabolism is converted to H2CO3

  • Dissociation of H2CO3 produces protons
  • Promote the release of oxygen

In the tissues

bohr effect1
Bohr effect

Oxygen binds to Hb, causing a release protons, which combine with bicarbonate to form H2CO3

Carbonic anhydrase cleaves H2CO3 to H2O and CO2

CO2 is exhaled

In the lungs


Hemoglobin determination


2. Direct spectrophotometry of plasma 415 – 460 nm

derivatives of hemoglobin
Derivatives of hemoglobin
  • Deoxyhemoglobin – Hb without O2
  • Oxyhemoglobin – Hb with O2
  • Carbaminohemoglobin – Hb with CO2

– CO2 is bound to globin chain

– about 15% of CO2 is transported in blood bound to Hb

  • Carbonylhemoglobin – Hb with CO

– CO binds to Fe2+ 200x higher affinity to Fe2+ than O2 – poisoning, smoking


Autooxidation of hemoglobin

3% of hemoglobin undergoes oxidation every day

Hem – Fe2+- O2 Hem - Fe3+ + O2•-

Methemoglobin reductase

reduces methemoglobin

FAD, cytochrom b5 a NADH


1. Hereditary deficit of methemoglobin reductase

2. Abnormal hemoglobin HbM (Hb mutation)

3. Exposure to exogenous oxidizing drugs (sulfonamides, aniline)

Clinical aspects: cyanosis (10% Hb forms metHb)

treatment: administration of methylene blue or ascorbic acid

  • Methemoglobin– (metHb) contains Fe3+ instead of Fe2+

Glycohemoglobin (HbA1c)

  • Formed by Hb‘s exposure to high levels of glucose
  • Nonenzymatic glycation of terminal NH2 group (Val) β-chain
  • Normally about 5% of Hb is glycated (proportional to blood Glc concentration)
  • People with DM have more HbA1c than normal ( 5%)
  • Measurement of blood HbA1c is useful to get information about long-term control of glycemia
  • mutation → abnormal structure of the hemoglobin
  • Large number of haemoglobin mutations, a fraction has deleterious effects: sickling, change in O2 affinity, heme loss or dissociation of tetramer
  • hemoglobin M and S, thalassemias

1. Hemoglobin M

    • Replacement of His E7α by Tyr (Hb Boston) or
    • Replacement of Val E11β by Glu (Hb Milwaukee)
    • the iron in the heme group is in the Fe3+ state (methemoglobin) stabilized by the tyrosine or by glutamate
    • Methemoglobin reductase cannot reduce Fe3+
    • methemoglobin can not bind oxygen

2. Thalassemias

    • Mutation that results in decreased synthesis of α or β-chains
    • thalassemia mutations provide resistence to malaria in the heterozygous state

α- thalassemias – complete gene deletion

  • 4 α globin genes per cell:
    • 1 copy of gen is deleted: without symptoms
    • 2 copies are deleted: RBC are of decreased size (microcytic) and reduced Hb concentration (hypochromic), individual is usually not anemic
    • 3 copies are deleted: moderately severe microcytic hypochromic anemia with splenomegaly
    • 4 copies are deleted: hydrops fetalis: fatal in utero

Excess β chains form homotetramer HbH which is useless for delivering oxygen to the tissues (high oxygen affinity)


β- thalassemias

  • β+ – some globin chain synthesis
  • β0 – no globin chain synthesis

Heterozygotes: microcytic hypochromic RBC, mild anemia

Homozygotes β0 β0 : severe anemia

Excess α chains precipitate in erythroid precursor – their destruction-ineffective erythropoiesis


3. Hemoglobin S (sickle-cell)

      • Causes a sickle-cell anemia
      • ReplacingGlu A3β withthelesspolaraminoacid Val - forming „anadhesive region“
      • oftheβ chain
      • HbSproteinsaggregateinto a longrodlikehelicalfiber

Sickle-cell anemia

Red blood cells adopt a sickle shape in a consequence of the forming haemoglobin S fibers

The high incidence of sickle-cell disease coincides with a high incidence of malaria

Individuals heterozygous in HbS have a higher resistance to malaria; the malarial parasite spends a portion of its life cycle in red cells, and the increased fragility of the sickled cells tends to interrupt this cycle


Pictures used in the presentation:

  • Marks´ Basic Medical Biochemistry, A Clinical Approach, third edition, 2009 (M. Lieberman, A.D. Marks)
  • Principles of Biochemistry, 2008, (Voet D, Voet J.G., and Pratt C.W)
  • Color Atlas of Biochemistry, second edition, 2005 (J. Koolman and K.H. Roehm)