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Pathophysiology of Heme Synthesis Beth A. Bouchard BIOC 212: Biochemistry of Human Disease Spring 2006 PowerPoint Presentation
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Pathophysiology of Heme Synthesis Beth A. Bouchard BIOC 212: Biochemistry of Human Disease Spring 2006. HEME-CONTAINING PROTEINS  Hemoglobin  Myoglobin  Cytochromes  Catalase  Some peroxidases. STRUCTURE OF HEME. An Overview of Iron Metabolism.

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slide1

Pathophysiology of Heme Synthesis

Beth A. Bouchard

BIOC 212: Biochemistry of Human Disease

Spring 2006

slide2

HEME-CONTAINING PROTEINS

 Hemoglobin

 Myoglobin

 Cytochromes

 Catalase

 Some peroxidases

an overview of iron metabolism
An Overview of Iron Metabolism
  • Low pH of stomach solubilizes Fe-containing ionic compounds.
  • Fe transporters facilitate absorption into blood stream

Gut

  • Fe3+ ions are bound and chelated by Transferrin (Tf).
  • Transferrin transports Fe to tissues
    • Maintains solubility
    • Keeps Fe ions unreactive

Blood

  • Transferrin endocytosis is receptor-mediated (TfR)
  • Endocytosis results in Fe3+ release
  • Fe is distributed to topologically distinct regions of the cell via Fe transporter and/or channels (?)
      • Usage: Protein components (Heme)
      • Storage: Ferritin (Fe2+)
      • Toxicity

Cells

roles of iron in the cell
Roles of Iron in the Cell

Fe(III)2-Tf Tf

Transferrin

Receptors (TfR)

Proteins: Catalysis

Electron, oxygen transport

Structural stabilization

Sensor of Fe, ROS

Formation of protein-bound radicals

[Fe]

Storage and Sequestration: Ferritin

[Fe]

Toxicity: Oxidative stress

[Fe]

slide6

Iron Control of Translation

IRE

  • IREs are found in the 5’-UTR or the 3’-UTR of mRNAs
  • Regulate mRNA translation via IRBP
  • Decreased cellular iron levels:
    • IRBP is free of iron and can therefore, interact with the IREs in the 3'-UTR of the transferrin receptor (TfR) mRNA, which prevents its degradation.
    • IRBP binds to the IRE in the 5’-UTR of the ferritin mRNA preventing its translation.
  • Increased cellular iron levels:
    • IRBP binds iron and cannot interact with the IREs in the TfR mRNA resulting in an increase in its degradation.
    • IRBP cannot bind to the IRE in the ferritin mRNA allowing for its translation.
slide7

STRUCTURE OF HEME

  • Ferrous iron (Fe2+)
  • Protoporphyrin IX: contains 4 pyrrole rings linked together by methenyl bridges
slide8

8

Succinyl CoA

Glycine**

8

HEME SYNTHESIS

Heme

** Amino acid (building blocks of protein) synthesized in your body

slide9

Heme

synthesis

heme synthesis red blood cells
HEME SYNTHESIS: Red blood cells
  • 85% of total heme synthesis occurs in red blood cells (RBC)
  • Ceases when RBC’s mature
  • Erythroid-specific ALA synthase is regulated by an IRE in the mRNA – binding of IRBP inhibits mRNA translation
slide13

HCI = heme controlled

inhibitor

Reduced initiation of translation

slide14

In RBCS, heme synthesis is also regulated at the level of the en-zymes ferrochelatase* and porphobilinogen deaminase**

*

**

heme synthesis liver
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
Formation of 5-aminolevulinate (5-ALA)

5-ALA

 5-ALA is formed in the mitochondria and transported

to the cytoplasm

slide17

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
Disorders of Heme Synthesis
  • Acquired: Lead poisoning
  • Congenital: Porphyrias
  • Deficiency of heme has far-reaching effects (hemoglobin, cytochromes, etc.)
lead toxicity
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 (PBG synthase & ferrochelatase)

 One symptom of lead toxicity is increases in 5-ALA without concomitant increases in PBG

porphyrias
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
acute intermittent porphyria
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
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