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Hematology 425, RBC Metabolism, Hgb and Iron

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The arrangement of amino acids also helps iron stay in the ferrous form ... to bind oxygen readily in the lung, transport oxygen, and unload oxygen in the tissues ... – PowerPoint PPT presentation

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Title: Hematology 425, RBC Metabolism, Hgb and Iron


1
Hematology 425, RBC Metabolism, Hgb and Iron
  • Russ Morrison
  • October 3, 2006

2
RBC Metabolism, Hgb and Iron
  • The RBC survives for approximately 120 days
    through the process of glycolysis
  • The main function of the RBC is transport of
    oxygen and CO2 to and from the tissues this
    function does not require consumption of energy
    (ATP)
  • RBCs lack a nucleus and other organelles and can
    not utilize proteins and lipids for energy they
    obtain energy only from carbohydrates through the
    EM pathway

3
RBC Metabolism, Hgb and Iron
  • RBC Process which Require Energy
  • Maintenance of intracellular cationic
    electrochemical gradients (Na, K, Ca pump and
    equilibrium)
  • Maintenance of membrane phospholipid
  • Maintenance of skeletal protein plasticity
  • Maintenance of ferrous hemoglobin
  • Protection of cell proteins from oxidative
    denaturation

4
RBC Metabolism, Hgb and Iron
  • RBC Process which Require Energy
  • Initiation and maintenance of glycolysis
  • Synthesis of glutathione
  • Mediation of nucleotide salvage reactions

5
RBC Metabolism, Hgb and Iron
  • RBC energy is stored and available as ATP, ADP
    and AMP review structure calorie bank
  • Glycolysis generates ATP from ADP and ATP is the
    greatest reservoir of energy in the RBC
  • 15 of ATP production is consumed through
    membrane exchange pathways that allow maintenance
    of Na, K, Ca levels
  • High K and low Na and Ca intracellularly and
    low K and high Na and Ca extracellularly.
  • If deprived of ATP energy, cation balance goes
    awry, the RBC swells and is destroyed

6
RBC Metabolism, Hgb and Iron
  • Plasma glucose enters the RBC glucose catabolic
    process through facilitated membrane transport.
  • 90-95 of glucose consumption is anaerobic
    through the EM pathway.
  • Through the EM pathway, glucose is metabolized to
    lactic acid using 2 ATP and generating 4 ATP
    molecules per molecule of glucose for a net gain
    of 2 ATP.

7
RBC Metabolism, Hgb and Iron
  • A diversion shunt off the EMP (Luebering-Rapaport
    pathway) provides 2,3-BPG.
  • 2,3-BPG regulates O2 delivery to tissues
  • The methemoglobin reductase pathway, another EMP
    bypass, produces NADH
  • NADH helps maintain hemoglobin in the
    functionally reduced state.

8
RBC Metabolism, Hgb and Iron
  • 5-10 of glucose consumption occurs through
    aerobic glycolysis through another diversion
    pathway hexose monophosphate pathway.
  • The hexose monophosphate pathway provides a pool
    of reduced glutathione to combat potential
    oxidant injury to the RBC

9
RBC Metabolism, Hgb and Iron
  • The enzyme deficiency in the EMP responsible for
    most cases of hereditary nonspherocytic hemolytic
    anemia is pyruvate kinase
  • The enzyme within the hexose monophosphate
    pathway that is most likely to give rise to
    deficient HMP function is G-6-PD

10
RBC Metabolism, Hgb and Iron
  • Hemoglobin
  • The Hgb molecule consists of four heme groups and
    two pairs of UNLIKE polypeptide chains
  • Hgb is the main component of the red blood cells,
    its concentration within the red blood cells is
    around 34 g/dL
  • Hgb is a red pigment with mw of 68,000 daltons
  • The vehicle for O2 transport in the body

11
RBC Metabolism, Hgb and Iron
  • See figure 9-2 of text
  • Heme consists of a ring of carbon, hydrogen and
    nitrogen (protoporphyrin IX) with an atom of
    ferrous (Fe2) iron attached, entire structure is
    called ferroprotoporphyrin.
  • Each heme group is positioned in a pocket of the
    polypeptide chain near the surface of the Hgb
    molecule.
  • Heme combines reversibly with one O2 molecule
  • Heme gives blood its red pigment

12
RBC Metabolism, Hgb and Iron
  • The globin of the hemoglobin molecule is made up
    of two pairs of polypeptide chains
  • Chains are 141-146 amino acids each
  • Variations in the amino acid sequence give rise
    to different types of polypeptide chains
  • Each type of polypeptide chain is designated by a
    Greek letter

13
RBC Metabolism, Hgb and Iron
14
RBC Metabolism, Hgb and Iron
  • See figure 9-3each polypeptide chain is divided
    into eight helices and 7 nonhelical segments
  • Helices are designated A to H and are rigid and
    linear
  • Nonhelical segments are more flexible and lie
    between the helical segments, designated NA, CD,
    etc. through HC

15
RBC Metabolism, Hgb and Iron
  • Globin chains are looped to form a cleft pocket
    for heme
  • Heme is suspended between the E and F helices
  • The Fe at the center of the protoporphyrin IX
    ring forms a bond with F8 and through the linked
    oxygen with E7
  • Amino acids in this cleft are hydrophobic and
    each chain contains a heme group with iron
    positioned between two histidine radicals

16
RBC Metabolism, Hgb and Iron
  • Amino acids on the outside of the cleft are
    hydrophilic, making the molecule water-soluble
  • The arrangement of amino acids also helps iron
    stay in the ferrous form
  • The complete hgb molecule is spherical, has 4
    heme groups attached to 4 polypeptide chains and
    may carry up to 4 oxygen molecules

17
RBC Metabolism, Hgb and Iron
  • The biosynthesis of heme takes place in the
    mitochondria and cytoplasm of the RBC precursors
    from pronormoblast to reticulocyte in the bone
    marrow.
  • Mature RBCs can not make hgb because they have no
    mitochondria and lose the capability of using the
    tricarboxylic acid cycle necessary for hgb
    synthesis

18
RBC Metabolism, Hgb and Iron
  • Assembly of heme occurs at the mitochondria where
    protoporphyrin IX is built.
  • Transferrin carries iron in the ferric (Fe3)
    form to developing RBCs
  • Fe goes through the RBC membrane to the
    mitochondria and is united with protoporphyrin IX
    to make heme
  • Heme leaves the mitochondria and is joined to
    globin chains in the cytoplasm.

19
RBC Metabolism, Hgb and Iron
  • 6 genes control synthesis of 6 globin chains
  • Alpha and zeta genes are on C16
  • Gamma, beta, delta and epsilon genes are on C11
  • Each set of single chains is synthesized in equal
    amounts at the ribosomes
  • Globin chains are released from the ribosomes
    into the cytoplasm

20
RBC Metabolism, Hgb and Iron
  • In the cytoplasm, globin chains bind hemes and
    then pair off
  • An alpha chain and non-alpha chain combine to
    form dimers
  • 2 dimers combine to form tetramers, completing
    the hemoglobin molecule
  • 2 alpha and 2 beta chains in a Hgb molecule is
    called HgbA
  • 2 alpha and 2 delta is Hgb A2, while 2 alpha and
    2 gamma is HgbF.
  • Globin chains exhibit different charge and may be
    separated electrophoretically

21
RBC Metabolism, Hgb and Iron
  • Progression of Hgb Production see figure 9-6
    and table 9-2
  • Hemoglobin F, predominant in-utero, has a higher
    affinity for oxygen and is able to extract
    oxygen across the placenta from the mother to the
    fetus

22
RBC Metabolism, Hgb and Iron
  • A modified form of hemoglobin A is formed by
    postsynthetic, nonenzymatic reactions of sugars
    with amino groups of the globin chains, Hgb A1.
  • The most common form of modified Hgb A1 is Hgb
    A1c in which glucose is added to the N terminus
    of the beta chain.
  • Hgb A1c is normally 4-6 of Hgb A and is an
    important marker in management of diabetes (A1c
    becomes increased and reflects management during
    span of RBC life cycle)

23
RBC Metabolism, Hgb and Iron
  • Regulation of hemoglobin production
  • Regulation of heme takes place in the heme
    production pathway
  • Rate limiting step is thought to be the initial
    formation of aminolevulinic acid (ALA)
  • ALA synthesis is inhibited by heme leading to
    decreased heme production (negative feedback)
  • Other feedback mechanisms may play a role

24
RBC Metabolism, Hgb and Iron
  • Regulation of hemoglobin production
  • Globin production is regulated by the rate at
    which the DNA code is transcribed to mRNA
  • The amount of globin produced is proportional to
    the amount of mRNA
  • Heme (hemin) controls the rate of globin
    synthesis in intact reticulocytes and in its
    absence, globin production decreases
  • Normal mature RBCs contain complete Hgb molecules
    and pools of free heme or free globin chains are
    minute.

25
RBC Metabolism, Hgb and Iron
  • Hgb synthesis is stimulated by tissue hypoxia
  • Hypoxia causes the kidneys to produce increased
    EPO which in turn stimulates production of Hgb
    and RBCs
  • Hgb Reference ranges
  • adult male 14.0-18.0 g/dL
  • adult female 12.0-15.0 g/dL
  • newborn 16.5-21.5 g/dL

26
RBC Metabolism, Hgb and Iron
  • The function of Hgb is to bind oxygen readily in
    the lung, transport oxygen, and unload oxygen in
    the tissues
  • The affinity of Hgb for oxygen depends on pH, 2,3
    BPG, pCO2, temperature, Hgb variants.
  • Review oxygen dissociation curve, figure 9-7
  • Shifts in the oxygen dissociation curve due to pH
    is known as the Bohr effect.

27
RBC Metabolism, Hgb and Iron
  • Iron
  • Iron is essential for sustained life in all
    living organisms except Lactobacillus and
    Bacillus species.
  • Most functional iron in humans is in hemoglobin
    or myoglobin,, which carry oxygen
  • About one fourth of iron is in a storage form

28
RBC Metabolism, Hgb and Iron
  • Functions of iron
  • Carrier of electrons used to bind with cofactors
    essential to basic metabolic oxidative and
    reductive reactions
  • Catalyst for oxygenation, hydroxylation and other
    metabolic processes
  • Ability to cycle between ferrous and ferric forms
    makes iron useful in many biochemical reactions

29
RBC Metabolism, Hgb and Iron
  • Iron must be carefully regulated due to its
    potential toxicity
  • Regulation is complex to preserve iron needed,
    while not allowing toxicity
  • Too little iron causes cellular functions to be
    suboptimal
  • Too much iron may produce organ damage and death

30
RBC Metabolism, Hgb and Iron
  • Iron status is dependent on iron intake, iron
    bioavailability and iron losses
  • We have mechanisms for absorbing dietary iron
    efficiently, but not for eliminating excess iron
    effectively
  • Understanding of molecular mechanisms involved in
    iron metabolism are just beginning to be
    understood

31
RBC Metabolism, Hgb and Iron
  • Iron is obtained through dietary means via heme
    (Fe2), organic and nonheme (Fe3), inorganic
    iron.
  • More iron is absorbed from the heme form of iron
    (meats) than from the nonheme form (legumes and
    leafy vegetables).
  • 5-35 of heme iron is absorbed from a meal, while
    2-20 of nonhem iron will be absorbed.

32
RBC Metabolism, Hgb and Iron
  • Maximal absorption of iron takes place in the
    duodenum and the jejunum.
  • Iron from food must be in the ferrous form to be
    bound to the enterocytes of the mucosal
    epithelium where it is internalized.
  • Review figure 10-1

33
RBC Metabolism, Hgb and Iron
  • Once absorbed, iron is transported in plasma
    bound to a carrier protein, transferrin.
  • Transferrin receptors located on all cells in the
    body (except mature RBCs), aid in providing
    transferrin-bound iron access into cells and also
    play a critical role in the release of iron from
    transferrin within the cell.
  • IRE-BP regulates the amoount of transferrin,
    transferrin receptor and ferritin in the body.
  • The transferrin gene is on C3

34
RBC Metabolism, Hgb and Iron
  • Ferritin and hemosiderin are storage forms of
    iron.
  • Most storage of iron is in the ferritin form, a
    water-soluble complex.
  • Hemosiderin is water-insoluble, made up of
    ferritin aggregates and found in macrophages in
    the bone marrow and liver.

35
Laboratory Assessment of Iron
36
Additional Laboratory Tests
  • Bone Marrow or liver biopsy with specific
    staining and qualitative/semi-quantitative
    assessment of available/stored iron.
  • In BM, the type of iron in macrophages is
    hemosiderin, the degenerative product of ferritin
    molecules that have been incorporated into
    lysosomes of the macrophagees.
  • Reticulocytes in the bone marrow that contain
    iron are termed siderocytes.
  • Serum transferrin receptor analysis
  • Red cell protoporphyrin test
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