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    BIOSYNTHESIS & CATABOLISM OF

    HEMOGLOBIN

    Abdul Salam M. Sofro

    Faculty of MedicineYARSI University Jakarta

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    Learning objectives

    By the end of learning, students are

    expected to understand:

    Molecular structure and function of

    hemoglobin

    Biosynthesis of hemoglobin

    Catabolic process and the fate ofhemoglobin catabolic products

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    Hemoglobin in blood

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    Blood cells development

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    General

    Hemoglobin (four subunits) and its similarmolecule myoglobin (one subunit) are iron-

    containing heme proteins consists ofapoprote n non-prote n eme

    These heme proteins function in oxygenbinding, oxygen transport, electron transport &

    photosynthesis carried out by heme (a cyclictetrapyrrole) & its ferrous iron (at the center ofthe planar ring)

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    Hemoglobin structure

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    Hemoglobin function

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    The Molecular structure is similar toMyoglobin :

    MW 17,000 ; a monomer of protein with

    153 AA residues

    stores oxygen in red muscle tissue will be

    released under condition of oxygen

    deprivation (eg. Severe exercise) and usedby muscle mitochondria for ATP synthesis

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    75% of the AA residues are present in 8 -

    helix (helix A to H)

    Histidin F8 and E7 perform unique roles inoxygen n ng

    Oxygen-binding curve for myoglobin is

    hyperbolic

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    Hemoglobin:

    Transports oxygen, CO2 & protons

    Its allosteric properties results from its

    quaternary structures

    A tetramer composed of pairs of differentpolypeptides/subunits (, , , etc.

    globin chains) a pair of globin chain

    product of gene cluster in chromosome 11

    & a pair of globin chain product of gene

    cluster in chromosome 16

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    Hb binds 2 protons for every 4 oxygen

    molecules released & thus contributessignificantly to buffering capacity of blood

    increase in proton concentration promotes

    oxygen release, while increase in PO2

    .

    At the lungs, oxygenation of Hb is

    accompanied by expulsion and subsequent

    expiration of CO2Bohrs effect (a reversiblephenomenon with that in the peripheral

    tissues)

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    2,3-Bisphosphoglycerate (BPG) in Hb

    Formed from glycolytic intermediate 1,3-bisphosphoglycerate

    One molecule of BPG is bound per Hbtetramer in the central cavity the spaceis wide enough when Hb is in the T form(deoxygenated)

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    Binds more weakly to fetal Hb than toadult Hb

    Increase concentration of BPG lowers

    P50) increasing the ability of Hb torelease oxygen at the tissues

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    As CO2 is absorbed in the blood, the carbonic

    anhydrase (CA) in erythrocyte catalyzes the

    formation of carbonic acid, which in turn

    rapidly dissociate into bicarbonate and a

    proton. To avoid increasing the acidity of blood,

    protons this is carried out by Hb

    CO2 + H2O H2CO3HCO3- + H+CA spontaneous

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    Mutant human Hb

    Causes hemoglobinopathy (when biologic

    function is altered)

    Due to mutations in the gene that code for

    globin chains: Structurally abnormal Hb (HbM, HbS, HbE,

    HbC etc)

    Reduced synthesis of Hb (thalassemias) Diagnosed by special method (e.g. molecular

    diagnosis)

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    Batak

    Melayu

    Minang

    Bangka

    Dayak

    Banjar

    Palu

    Minahasa

    Toraja

    1,5 0

    3,7

    5,2

    2,9

    4,3

    5,44,5

    3,11,5

    0 1,7

    1,23,7

    Palembang

    Jawa

    Tengger

    SumbawaBali

    Sumba

    Sasak

    Alor

    Gambar . Pola distribusi dan prevalensi trait thalassemia- dan hemoglobin-E

    pada berbagai populasi di Indonesia. * adalah hemoglobin OIna

    .

    9,26,5

    3,2 4,8

    0 10,6

    0 0 0 4*

    1,26,1

    2,9 4,32,5 36,6

    5,1 6,8 0 0

    = trait thalassemia-

    = trait hemoglobin-E

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    Heme

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    In addition to the heme b found in hemoglobin,

    there are three different forms of heme found incytochromes such as those involved in the

    process of oxidative phosphorylation.

    Cytochromes of the c type contain a modified iron

    protoporphyrin IX known as heme c. In heme c

    the 2 vin l C=C side chains are covalentl

    bonded to cysteine sulfhydryl residues of the

    apoprotein. Only cytochromes of the c type

    contain covalently bound heme. Heme a is also a

    modified iron protoporphyrin IX. Heme a is foundin cytochromes of the a type and in the

    chlorophyll of green plants

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    Biosynthesis of heme

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    Protoporphyrin IX

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    The sythesis of heme is a

    complex process thatinvolves multiple

    enzymatic steps. The

    process begins in the

    mitochondrion with the

    condensation of succinyl- -

    aminolevulinic acid. A

    series of steps in the

    cytoplasm produce

    coproporphrynogen III,which re-enters the

    mitochondrion. The final

    enzymatic steps produce

    heme.

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    Synthesis Of Porphobilinogen and Heme

    http://themedicalbiochemistrypage.org/heme-porphyrin.html

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    Globin

    a polypeptide chain (protein)

    Various types of polypeptide chain:

    Alpha globin

    Gamma globin

    Delta globin

    Epsilon globin Zetta globin

    Teta globin

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    Globin Genes

    Chromosome 11

    (- cluster):

    -G -A - --

    Chromosome 16

    (-cluster):

    2-1-2-1-2-1-

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    2 21 1 1

    Globin Genes :

    5' 3'

    Chromosome #16

    2 22 22 2Hb types :

    Embryo

    (Gower-I) (Portland) (Gower-II)

    Chains Synthesized

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    3'5' G A

    Globin Genes :

    Chromosome #11

    2 2 222 2 2 2

    Fetus Adult

    (Hb-F)(Hb-A ) (Hb-A)2

    G

    G

    A

    A

    Hb types :

    Chains Synthesized

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    50

    % of totalglobinsynthesis

    10

    6 18 30 6 18 30 42

    prenatal age (wks)

    birth

    postnatal age (wks)

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    Types of Hemoglobin

    Hb Gower 1 = 22

    Hb Portland = 22 ower =

    Hb Fetal (HbF) = 22

    Hb Adult (HbA) =

    2

    2

    Hb Adult minor (HbA2) = 22

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    Catabolism of Heme

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    Heme Breakdown

    During its 120 day life span the

    erythrocyte has traveled 200-300 miles.

    The process of aging is calledsenescence.

    Enzyme activity decreases (esp.

    glycolytic enzyme which helps break

    down glucose, the source of

    erythrocyte energy), and the cell looses

    its deformability.

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    MCHC (mean corpuscular hemoglobinconcentration) increases, the cell

    becomes rounder, and the MCV mean

    corpuscular volume) decreases.

    Erythrocytes occurs by extravascular

    hemolysis. Macrophages of the

    mononuclear phagocyte system removethem from circulation.

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    Macrophages of the spleen are especiallyactive in removing aging, dead and abnormal

    erythrocytes (e.g. cells containing Heinz

    bodies or Howell-Jolly bodies, siderocytes,, ,

    antibody-coated erythrocytes).

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    Normally, Senescent Red Blood Cells and Heme

    from other Sources are Engulfed by Cells of the

    Reticuloendothelial System. The Globin isRecycled or Converted into Amino Acids,

    Which in turn are Recycled or Catabolized as

    Required.

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    Heme is Oxidized, with the Heme Ring

    Being Opened by the Endoplasmic

    Reticulum Enzyme, Heme Oxygenase.

    a Substrate, and any Hemin (Fe3+) is

    Reduced to Heme (Fe2+) Prior to

    Oxidation by Heme Oxygenase

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    Pathway for the

    degradation ofheme to