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    Heme Metabolism TAU

    Uploaded by

    Faatimah Essa
    This document provides an outline on heme metabolism. It discusses: 1) Heme synthesis, which takes place in the mitochondria and cytosol and involves the condensation of glycine and succinyl-CoA to form delta-aminolevulinic acid (ALA). 2) Heme breakdown, in which heme is broken down to bilirubin. 3) Bilirubin metabolism, where bilirubin is conjugated and excreted in the bile or urine. The key steps in heme synthesis include the formation of porphobilinogen from ALA, the synthesis of uroporphyrinogen from porphobilinogen, and the incorporation of

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    Heme Metabolism TAU

    Uploaded by

    Faatimah Essa
    7 views23 pages
    This document provides an outline on heme metabolism. It discusses: 1) Heme synthesis, which takes place in the mitochondria and cytosol and involves the condensation of glycine and succinyl-CoA to form delta-aminolevulinic acid (ALA). 2) Heme breakdown, in which heme is broken down to bilirubin. 3) Bilirubin metabolism, where bilirubin is conjugated and excreted in the bile or urine. The key steps in heme synthesis include the formation of porphobilinogen from ALA, the synthesis of uroporphyrinogen from porphobilinogen, and the incorporation of

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    This document provides an outline on heme metabolism. It discusses: 1) Heme synthesis, which takes place in the mitochondria and cytosol and involves the condensation of glycine and succinyl-CoA to form delta-aminolevulinic acid (ALA). 2) Heme breakdown, in which heme is broken down to bilirubin. 3) Bilirubin metabolism, where bilirubin is conjugated and excreted in the bile or urine. The key steps in heme synthesis include the formation of porphobilinogen from ALA, the synthesis of uroporphyrinogen from porphobilinogen, and the incorporation of

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    7 views23 pages

    Heme Metabolism TAU

    Uploaded by

    Faatimah Essa
    This document provides an outline on heme metabolism. It discusses: 1) Heme synthesis, which takes place in the mitochondria and cytosol and involves the condensation of glycine and succinyl-CoA to form delta-aminolevulinic acid (ALA). 2) Heme breakdown, in which heme is broken down to bilirubin. 3) Bilirubin metabolism, where bilirubin is conjugated and excreted in the bile or urine. The key steps in heme synthesis include the formation of porphobilinogen from ALA, the synthesis of uroporphyrinogen from porphobilinogen, and the incorporation of

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    of 23

    Medical Biochemistry & Genetics (MBG1125)

    Metabolism of Heme
    by

    Dr. Chimuka Mwaanga


    Heme Metabolism (Outline)
    Heme (Haem) Synthesis

    Heme Breakdown

    Bilirubin Metabolism
    Heme Molecular Structure

    N
    H
    pyrrole

    pyrrole rings

    • Heme is a derivative of the porphyrin molecule.


    • Porphyrins are cyclic compounds formed by fusion of 4
    pyrrole rings linked by methenyl bridges.
    Heme is a Derivative of Porphyrin
    (C20H14N4)

    Heme
    Porphyrin
    Biological Importance of Heme

    Heme is the prosthetic group of hemoproteins


    Hemeglobin (α2β2): The Oxygen Carrier
    because of Heme

    Heme (Haem) and ferrous Iron confer the ability to store


    and transport Oxygen
    Heme Biosynthesis
    Synthesis of Heme
    • The substrates mainly include succinyl-CoA,
    glycine, Fe2+.
    • Heme can be synthesized by almost all the tissues
    in the body which require hemoproteins.
    • Major sites of synthesis is liver and bone marrow
    • The whole synthetic process takes place
    subcellularly in the mitochondria and cytosol
    Step 1
    In mitochondrion

    ① Heme synthesis begins with condensation of


    glycine & succinyl-CoA, with decarboxylation, to
    form d-aminolevulinic acid (ALA).
    ALA Synthase is The Regulatory Enzyme for Heme
    Biosynthesis
    1. ALA Synthesis is the committed step of the heme synthesis
    pathway, and usually rate-limiting for the overall pathway.
    2. Regulation occurs through control of gene transcription.
    3. Heme functions as a feedback inhibitor, repressing transcription
    of the ALA Synthase gene in most cells.
    Step 2 COOH O
    OH
    CH2 porphobilinogen
    CH2 HO

    O C
    ALA dehydratase
    O
    H C H
    2H2O
    H N H N
    H2N H

    • The succeeding few reactions occur in the cytoplasm.


    • One ALA condenses with another molecule of ALA to form porphobilinogen(PBG).
    • The condensation involves removal of 2 molecules of water and the enzyme is
    ALA dehydratase .
    COO

    COO CH2 Porphobilinogen


    CH2 CH2 (PBG) is the first
    pathway intermediate N
    that includes a H
    H2 C pyrrole ring. pyrrole
    N
    + H
    NH3
    Porphobilinogen (PBG)
    The porphyrin ring is formed by condensation of 4 molecules of
    porphobilinogen.
    Porphobilinogen Deaminase catalyzes successive PBG condensations,
    initiated in each case by elimination of the amino group.
    Synthesis of Uroporphyrinogen from PBG
    URO

    COPRO
    PROTO
    CH2 protoporphyrin IX CH2 heme
    CH CH3 CH CH3

    H3C CH CH2 H3C CH CH2


    NH N ++ +
    N N
    Fe 2H
    Fe
    N HN N N
    H3C CH3 H3C CH3

    CH2 CH2 Ferrochelatase CH2 CH2

    CH2 CH2 CH2 CH2


    - - - -
    COO COO COO COO

    - heme is formed by incorporation of iron (Fe2+)


    - partly spontaneous
    - ferrochelatase enhances rate and also inhibited by lead
     Fe++ is added to protoporphyrin IX via Ferrochelatase, a homodimeric enzyme
    containing 2 iron-sulfur clusters.
    Regulation of heme synthesis
    Regulation of heme synthesis

    1. ALA synthase
    Major site of regulation is at the level of ALA synthase.

    ① It is regulated by repression mechanism.


    Heme inhibits the synthesis of ALA synthesis by
    acting as a corepressor. The feedback regulatory
    effect is a typical example of end-product
    inhibition.
    ② ALA synthase is also allosterically inhibited by
    hematin.
    When there is excess of free heme without globin
    chains to bind with, the Fe++ is oxidized to Fe+++
    forming hematin. Hematin will inhibit ALA synthase
    to prevent excessive unwanted production of heme.

    Hematin will also inhibit the translocation of ALA


    synthase from the cytoplasm into the mitochondria where
    its substrate, succinyl CoA is formed. Thus heme synthesis
    is inhibited till there are sufficient globin chains to bind with.
    ③ Lack of Vitamin B6 will decrease the synthesis of
    ALA.
    Drugs like INH (isonicotinic acid hydrazide) that
    decrease the availability of pyridoxal phosphate may
    also affect heme synthesis.
    2. Heme synthesis may be inhibited by heavy metals. the steps
    catalyzed by ALA dehydratase and ferrochelatase are inhibited by lead.

    3. erythropoietin, EPO

     The kidneys also secrete a hormone called erythropoietin.


     The function of erythropoietin is to stimulate the production of red blood cells. The
    kidney produces 85~95% of the body's erythropoietin so when the kidney is
    damaged (kidney disease or failure), not enough erythropoietin is produced to
    maintain normal red blood cell levels. This leads to anemia.
    Heme Breakdown and Bilirubin
    Metabolism
    Heme Degradation
    Bilirubin
    Metabolism

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