212_spring_2005_heme synthesis by stariya

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									Pathophysiology of Heme Synthesis


           Beth A. Bouchard
BIOC 212: Biochemistry of Human Disease
              Spring 2005
     HEME-CONTAINING PROTEINS


 Hemoglobin

 Myoglobin

 Cytochromes

 Catalase

 Some peroxidases
Iron Utilization
STRUCTURE OF HEME


           • Ferrous iron (Fe2+)

           • Protoporphyrin IX:
             contains 4 pyrrole
             rings linked together
             by methenyl bridges
                    HEME SYNTHESIS



8
            Succinyl CoA



8            Glycine**



                                                             Heme


** Amino acid (building blocks of protein) synthesized in your body
Heme
synthesis
HEME SYNTHESIS
        HEME SYNTHESIS: Red blood cells

•85% of total heme synthesis
occurs in red blood cells (RBC)

•Ceases when RBC’s mature

•Heme stimulates protein
synthesis in reticulocytes


Synthesis is regulated at the
level of the enzymes
ferrochelatase* and
porphobilinogen deaminase**
*
    **
        HEME SYNTHESIS: Liver

•The liver is the main non-RBC source of heme
synthesis

•Heme produced in the liver is used mainly for the
synthesis of the cytochrome P450 class of enzymes
that are involved in detoxification

Regulated at level of ALA synthase: Formation of 5-
ALA is the rate-limiting step in heme synthesis in
the liver
  Formation of 5-aminolevulinate (5-ALA)




                            5-ALA


 5-ALA is formed in the mitochondria and transported
to the cytoplasm
      Regulation of ALA Synthase
Level of enzyme synthesis

       Enzyme synthesis, as well as its transport to the
       mitochondria, is inhibited by elevated levels of heme and
       hemin, the Fe3+ oxidation product of heme

       Enzyme synthesis is upregulated by a large number of
       drugs including barbiturates, steroids with a 4,5 double
       bond (e.g. testosterone) and some oral contraceptives:
       These drugs are metabolized by the microsomal
       cytochrome P450 mono-oxygenase system, a heme-
       containing protein.

Level of enzyme activity

       Heme and hemin inhibit ALA synthase activity

       Requires pyridoxal phosphate (Vitamin B6) as a
       coenzyme
    Disorders of Heme Synthesis


• Acquired: Lead poisoning

• Congenital: Porphyrias

• Deficiency of heme has far-reaching effects
(hemoglobin, cytochromes, etc.)
               LEAD TOXICITY

Symptoms
       Irritibility         Poor appetite
       Lethargy             Abdominal pain (with or
       Sleeplessness       without vomiting)
       Headaches            Constipation



Pathophysoiology
       Binds to any compound with a sulfhydryl group
       Inhibits multiple enzyme reactions including those
      involved in heme biosynthesis (ALA synthase &
      ferrochelatase)
       One symptom of lead toxicity is increases in 5-ALA
      without concomitant increases in PBG
HEME SYNTHESIS (CONT.)



        Vitamin
        B6


lead
                        PORPHYRIAS
 A group of rare disorders caused by deficiencies of enzymes of the
heme biosynthetic pathway

The majority of the porphyrias are inherited in a autosomal dominant
fashion - thus, affected individuals have 50% normal levels of the
enzymes, and can still synthesize some heme

Affected individuals have an accumulation of heme precursors
(porphyrins), which are toxic at high concentrations

Attacks of the disease are triggered by certain drugs, chemicals, and
foods, and also by exposure to sun

 Treatment involves administration of hemin, which provides negative
feedback for the heme biosynthetic pathway, and therefore, prevents
accumulation of heme precursors
Scriver et al., The Metabolic & Molecular Basis of Inherited Disease, 8th edition, 2001.
 ACUTE INTERMITTENT PORPHYRIA


 Hepatic, autosomal dominant

 Caused by a deficiency in porphobilinogen
deaminase, which is involved in the conversion of
porphobilinogen (PBG) to uroporphyrinogen III

PBG, uroprophryin, and 5-ALA accumulate in the plasma
and the urine

Patients have neuropyschiatric symptoms and
abdominal pain (neurovisceral)
  PORPHYRIA CUTANEA TARDA
Most common porphyria

Hepatic, autosomal dominant

Disease is caused by a deficiency in uroporphyrinogen
decarboxylase, which is involved in the conversion of
uroporphyrinogen III to coproporphyrinogen III

 Uroporphyrinogen accumulates in urine

 Patients are photosensitive (cutaneous photosensitivity)
         Accumulation of porphyrinogens results in their
         conversion to porphyrins by light

        Porphyrins react with molecular oxygen to form
        oxygen radicals

        Oxygen radicals can cause severe damage to the
        skin

								
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