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    Haemoglobin Synthesis

    Uploaded by

    Uche Emmanuel
    Each hemoglobin molecule is made up of four heme groups with iron atoms at their centers attached to four globin protein chains. Hemoglobin and its subunits are synthesized simultaneously but in different cellular locations - heme is produced in mitochondria while globin chains are produced by ribosomes in the endoplasmic reticulum. The iron-containing heme groups combine with the globin chains to form functional hemoglobin molecules, which transport oxygen and carbon dioxide via allosteric effects of binding these gases and other small molecule effectors like 2,3-DPG and pH levels.

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    Haemoglobin Synthesis

    Uploaded by

    Uche Emmanuel
    52 views28 pages
    Each hemoglobin molecule is made up of four heme groups with iron atoms at their centers attached to four globin protein chains. Hemoglobin and its subunits are synthesized simultaneously but in different cellular locations - heme is produced in mitochondria while globin chains are produced by ribosomes in the endoplasmic reticulum. The iron-containing heme groups combine with the globin chains to form functional hemoglobin molecules, which transport oxygen and carbon dioxide via allosteric effects of binding these gases and other small molecule effectors like 2,3-DPG and pH levels.

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    Each hemoglobin molecule is made up of four heme groups with iron atoms at their centers attached to four globin protein chains. Hemoglobin and its subunits are synthesized simultaneously but in different cellular locations - heme is produced in mitochondria while globin chains are produced by ribosomes in the endoplasmic reticulum. The iron-containing heme groups combine with the globin chains to form functional hemoglobin molecules, which transport oxygen and carbon dioxide via allosteric effects of binding these gases and other small molecule effectors like 2,3-DPG and pH levels.

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    52 views28 pages

    Haemoglobin Synthesis

    Uploaded by

    Uche Emmanuel
    Each hemoglobin molecule is made up of four heme groups with iron atoms at their centers attached to four globin protein chains. Hemoglobin and its subunits are synthesized simultaneously but in different cellular locations - heme is produced in mitochondria while globin chains are produced by ribosomes in the endoplasmic reticulum. The iron-containing heme groups combine with the globin chains to form functional hemoglobin molecules, which transport oxygen and carbon dioxide via allosteric effects of binding these gases and other small molecule effectors like 2,3-DPG and pH levels.

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    of 28

    Structure & Synthesis of haemoglobin (Hb)

    Each Hb molecule is made up of:

    • 4 Haem/Heme: Protoporphyrin (Pyrrol ring) + Fe

    • Four Globin chains


    Haemoglobin (Hb)

    Each of the 4 polypeptide chains is attached


    to a haem moiety.

    • For example, the normal adult Hb (Hb A)


    has 2 alpha (a) & 2 beta (b) chains held
    together by non-covalent bonds.

    • Hb A = a2 b2
    Synthesis of Haemoglobin
    • Haem & globin are produced at two different sites in the cell

    • Haem in the mitochondria


    • Globin in ribosomes

    • Production of the 2 components of Hb occur simultaneously.


    Synthesis of Heme
    • The heme moiety is made up of a protoporphyrin ring with an iron
    atom attached at the centre.

    • The main site of synthesis is the mitochondria

    • Mature red cells do not have mitochondria


    Heme
    synthesis
    • Heme = Protoporphyrin + Iron
    • Protoporphyrin = Iron free Heme
    • Protoporphyrin consist of 4 pyrrol rings.
    • Iron has 6 coordinations, 4 binds with the 4 pyrrol rings of
    protoporphyrin, 1 binds with histidine (amino acid) from
    globin chain and 1 is free (bind to Oxygen, CO 2 respectively)
    Structure of Heme
    1) Heme synthesis start with 2 simple molecules in the mitochondria

    a. Glycine (amino acid)

    b. Succinyl Co-A (intermediate of citric acid cycle)

    2) Reaction of these 2 simple molecules with a co-factor (vitamin B6) will


    produce aminolevulinic acid (ALA Synthase)
    • This is the regulatory or rate limiting step of heme synthesis
    3. ALA exits the mitocondria into the cytoplasm where some
    steps occur to generate copropophyrinogen which enters back
    into the mitochondria to form protoporphyrinogen and then
    protoporphyrin.

    4. Protoporphyrin bind with iron (ferrous- Fe2+)

    At same time, globin is synthesized in the RER.


    Protoporphyrin + ferrous + globin chains will form haemoglobin.
    Synthesis of Haemoglobin
    • When O2 binds to iron, the process is called oxygenation
    not oxidation as oxygen is transported in circulation as a
    molecule (O2).

    • The oxidation state of iron rarely change. Oxidation of


    Fe2+ to Fe3+ occur only occasionally. The oxidized form,
    methemoglobin (1–2%), cannot bind to O2.
    Synthesis of globin
    Types of Haemoglobin (Normal)
    • Different types of Hb exist due to the type of globin
    chain present & NOT Heme.

    • Adults have and a small amount of its sub-type


    HbA HbA2.

    • Fetuses have HbF.


    Normal haemoglobin types
    • Fetal Hb: HbF (a2g2)

    • Adult Hb: HbA (a2b2)

    • Adult Hb: HbA2 ( a2d2)

     HbF has more affinity for oxygen than HbA.


    Normal Adult Haemoglobin
    Hb A Hb A2 Hb F

    Structure a2b2 a2d2 a2g2

    Normal % 96-98 % 1.5-3.2 % 0.5-0.8 %


    Abnormal haemoglobin
    types
    Qualitative defect in Hb
    Hb S: caused by a substitution of amino acid in β globin chain
    (valine for Glutamate).
    Hb C: caused by a substitution of amino acid in β globin chain
    (Lysine for Glutamate).
    Others: Hb D, E, G, H to T

    Quantitative defect in Hb (Thalasemias)


    Major: β- thalassemia major (absence of synthesis of β globin chain-
    no HbA (HbA2 & Hb F compensates).
    Minor: reduction in synthesis of globin chain (α or β)
    Normal & Abnormal
    Haemoglobin
    Gas transport by haemoglobin
    • Why is haemoglobin used as a transporter for gases? Because of the low
    solubility of oxygen & CO2 in fluid. Therefore, haemoglobin has a
    regulatory effect on oxygen concentration in the lungs and tissues.
    Allosteric effect
    • When a molecule reacts with conformational changes that increases or
    reduces its activity, it is said to show an allosteric behaviour.
    • Some substances act on Hb as allosteric substances.
    • Although Hb is NOT an enzyme, it exhibit this characteristic of enzymes.
    Substances that have an allosteric effect on Hb are:

    1. 2,3 DGP (intermediate factor in glycolysis)


    2. H+ ( i.e. pH)
    3. CO2
    Forms of
    Hb
    • When Hb show high affinity to oxygen in the lungs it is in the
    oxyhaemoglobin form refered to as the R form (R from Relax)
    • When Hb show low affinity for oxygen in the tissues, it is in the
    deoxyhaemoglobin form, refered to as T form (T from Tense)

    • Allosteric substances act as stabilizers for T form of Hb i.e. they


    affect the saturation of Hb with oxygen.
    Steps for O2- CO2
    Transport
    • In the lungs, the pressure of oxygen is high so it diffuses and
    binds with Hb (bond of one O2 to haemoglobin fascilitates
    the binding of other O2 molecules).

    • In the tissues, haemoglobin binds to 2,3 DPG causing a


    decrease in the affinity of Hb for O2, releasing oxygen to the
    tissues.
    • At the same time, CO2 binds to Hb due to high pressure of CO2 in
    the tissues, reducing Hb affinity to oxygen (allosteric effect).

    2,3 DGP enters between the two β chains and convert Hb from R
    to T form, reducing the affinity of Hb for oxygen, this cause the
    release of O2 (shift to the right on Hb dissociation curve)

    *Note : HbF has no affinity to 2,3DGP, making the affinity of HbF


    for oxygen more than HbA that has affinity for 2,3 DGP.
    H+ (pH) and CO2 :
    Formed from metabolic processes in tissues, bind to
    Hb and decrease the affinity of Hb for O2 (allosteric
    effect), this is also known as the Bohr effect.
    https://www.youtube.com/watch?v=b2hKDxX-KjE

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