Heme Metabolism

Heme Metabolism – Introduction

Heme is an essential molecule that is involved in a variety of biological processes, including oxygen transport, electron transport, and drug metabolism. Heme is synthesized in the body through a complex process known as heme biosynthesis, which involves multiple enzymes and regulatory pathways.

Heme is a porphyrin ring that contains an iron atom in the center. The iron atom is essential for the function of heme, as it allows the molecule to bind and transport oxygen and other small molecules. Heme is found in various proteins throughout the body, including hemoglobin in red blood cells, myoglobin in muscle cells, and cytochromes in the electron transport chain.

Heme synthesis

• Functions 
  • hemoglobin
  • cytochrome b₄
  • P450
• Location of synthesis
  • involves both the mitochondria and the cytosol
  • occurs in nearly every cell
    • occurs in RBC progenitor cells
      • CANNOT occur in RBCs because they lack mitochondria 
• Pathway
  • ALA synthase is rate limiting enzyme (see above)
• Deficiencies in heme synthesis
  • hemin
    • occurs when Fe³⁺ is incorporated instead of Fe²⁺
  • porphyria
    • causes
      • symptoms due toxic accumulation of pathway intermediates
        • aminolevulinic acid (ALA) causes neurological symptoms
        • protoporphyrins cause photosensitivity
          • conjugated structure what absorbs light energy and forms free radicals
      • symptoms worsened by
        • sunlight
        • P450 inducing drugs
          • stimulate the heme synthesis pathway to ↑ production
          • ex.) barbiturates, alcohol
    • treatment
      • limit exposure to sun and P450 inducing substances
      • hemin
        • inhibits new heme production
    • types
      • porphyria cutanea tarda
        • deficiency in uroporphyrinogen decarboxylase 
        • AD
        • late onset (4th or 5th decade)
          • symptoms often noticed with alcohol consumption
        • presentation
          • photosensitivity
          • hyperpigmentation
            • body’s attempt to protect the skin
          • dark red/brown colored urine
      • acute intermittent porphyria
        • deficiency in porphobilinogen deaminase 
        • AD
        • late onset
        • presentation
          • NO photosensitivity
          • episodic psychological symptoms (paranoia, anxiety, depression)
          • vague abdominal pain
            • patients can present with a history of laparoscopies
          • dark red/brown colored urine
            • ALA and porphobilinogen (PBG) present in urine during symptoms
  • poisoning
    • lead
      • induced deficiency in ALA dehydratase and ferrochelatase
        • both enzymes are Zn²⁺ dependent metalloenzymes
        • Pb²⁺ replaces the Zn²⁺ at the active site
      • presentation
        • ↓ in IQ
        • microcytic anemia with coarse basophilic stippling
        • abdominal pain
        • ↑ in ALA without ↑ in PBG
          • differentiates from porphyrias
        • lead lines in bone and teeth xrays
        • nephrotoxicity
          • deposition in nuclei of proximal renal tubular cells
    • hexachlorobenzene
      • induced deficiency in uroporphyrinogen decarboxylase
      • presentation
        • hypertrichosis (↑ body hair coverage)
      • found in (now banned in USA) pesticides
  • iron deficiency
    • iron incorporated in the final step
    • result is microcytic hypochromic anemia
    • see Trace metals topic
  • vitamin B₆ deficiency
    • rate limiting enzyme (ALA synthase) requires
    • most commonly due to isoniazid therapy
• see Vitamins topic

Degradation of Heme

• Function
  • rid body of hemoglobin removed from degraded RBCs
• Location of degradation
  • spleen
    • site of RBC destruction
  • liver
    • site of bilirubin conjugation
  • intestine
    • conversion by normal gut flora
• Pathway  

Bilirubin

• Properties
  • insoluble
    • must travel in blood bound to albumin
  • conjugation
    • direct (conjugated)
      • glucuronate group added
        • soluble
    • indirect (unconjugated)
      • glucuronate group not yet added
        • insoluble
• Modified forms
  • urobilinogen
    • gives urine yellow color
  • stercobilin
    • gives feces brown color
• with a blocked bile duct no stercobilin in feces and it is clay colored

Types – Heme Metabolism

There are two types of heme metabolism: catabolic and anabolic.

1. Catabolic heme metabolism: This is the breakdown of heme, which occurs primarily in the liver and spleen. The process starts with the enzyme heme oxygenase, which cleaves the porphyrin ring and releases iron, carbon monoxide, and biliverdin. Biliverdin is then converted to bilirubin, which is transported to the liver and conjugated with glucuronic acid. The conjugated bilirubin is then excreted in the bile and ultimately in the feces.
2. Anabolic heme metabolism: This is the synthesis of heme, which occurs mainly in the bone marrow and liver. Heme is synthesized from the precursor molecule, glycine, and succinyl CoA in a series of enzymatic reactions that involve multiple enzymes and regulatory pathways. The final product of heme synthesis is protoporphyrin IX, which combines with iron to form heme. Heme is then incorporated into various proteins, such as hemoglobin and cytochromes.

Studies – Heme Metabolism

The study of heme metabolism is essential for understanding the regulation and function of heme in the body, as well as for identifying and treating porphyria and other related disorders. Here are some notable studies related to heme metabolism:

1. Discovery of Heme Oxygenase: In 1968, Tenhunen and colleagues discovered the enzyme heme oxygenase, which catalyzes the rate-limiting step in heme catabolism. This discovery was crucial for understanding the mechanism of heme breakdown and for developing treatments for heme-related disorders.
2. Elucidation of Heme Biosynthesis Pathway: The biosynthesis of heme is a complex process that involves multiple enzymes and regulatory pathways. The elucidation of this pathway was a significant accomplishment in the field of biochemistry, as it allowed for the identification of genetic defects that cause porphyria and other heme-related disorders.
3. Gene Therapy for Porphyria: In recent years, gene therapy has been explored as a potential treatment for porphyria. In a 2020 study, researchers used a viral vector to deliver a corrected copy of the gene that encodes the enzyme uroporphyrinogen III synthase (UROS) to mouse models of congenital erythropoietic porphyria. The results showed a significant improvement in symptoms, indicating the potential of gene therapy as a treatment for porphyria.
4. Role of Heme in Cellular Signaling: Heme has been shown to play a role in cellular signaling, particularly in the regulation of inflammation and oxidative stress. A 2018 study found that heme can activate the NLRP3 inflammasome, a key mediator of inflammation, and that blocking this activation may have therapeutic potential for inflammatory diseases.

Overall, studies on heme metabolism have contributed significantly to our understanding of the regulation and function of heme in the body, as well as to the development of treatments for heme-related disorders.

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