Tetrapyrrole Synthesis: Heme Synthesis, Porphyrias, and Catabolism

Dr. Anastasios (Tasos) Tsaousis

Email: A.Tsaousis@kent.ac.uk

1. General Learning Objectives

• Metabolism is Interesting:

  • Metabolism operates on a foundation of chemical logic, demonstrating how biochemical pathways can be sequenced and modified for efficiency.

  • An illustrative example is the comparison between the synthetic pathways of adenine in chemical and biological systems, revealing the complexity and precision of enzymatic reactions.

• Control and Regulation:

  • Regulatory mechanisms are crucial for ensuring metabolic processes occur in response to physiological needs and environmental changes, highlighting the intricate feedback loops and signal transduction pathways involved.

• Resource Management:

  • Effective management of metabolic resources is vital, ensuring a consistent supply of substrates and cofactors necessary for sustaining metabolic reactions and overall cellular function.

2. Heme and Disease

Case Study:

• View an episode of House (S1E22) focusing on the condition known as Acute Intermittent Porphyria (AIP).

• Objectives:

  • Develop an understanding of how genotype (the underlying genetic cause) directly relates to phenotype (the observable symptoms), which is essential for diagnosing genetic disorders like AIP.

3. Symptoms of Acute Intermittent Porphyria (AIP)

According to House, symptoms include:

• Intermittent syndrome:Symptoms occur in episodes, sometimes triggered by environmental or lifestyle factors.

• Abdominal pain:Often severe, typically in the abdominal region, indicating potential complications or effects on surrounding organs.

• Mood swings and psychiatric symptoms:Range from irritability to severe psychiatric disturbances, including delusions and prolonged episodes of paranoia.

• Polyneuropathy:Manifestation includes muscle weakness and sensory disturbances, reflecting nerve involvement.

• Light sensitivity:Photosensitivity may lead to skin issues when exposed to sunlight due to porphyrin accumulation.

4. Diagnosis of AIP

Diagnosis according to House:

• Clues for Diagnosis:

  • Distinctive symptoms may aid in prompting further investigation, such as the absence of fingerprints.

• Urine and blood tests may initially yield inconclusive results.

• An accurate diagnosis requires capturing an acute attack live, ideally through urine tests conducted during an episode, which helps in detecting elevated levels of porphobilinogen (PBG) or other porphyrins.

5. Treatment of AIP

Treatment options according to House:

• Medications:

  • Hematin and glucose: Effective for managing AIP episodes by replenishing heme levels and decreasing porphyrin production.

  • Caution: Incorrect treatment can lead to acute complications and potentially be life-threatening.

• Triggers for Attacks:

  • Specific substances like barbiturates, alcohol, and certain protein intakes can provoke AIP attacks, advising patients to avoid these where possible.

• Testing during Treatment:

  • A urine test designed to include oxidation steps can provide insight into the effectiveness of treatment and the metabolic state of heme synthesis.

6. Structure of Heme

Chemical Structure:

• Heme is a modified tetrapyrrole consisting of four pyrrole rings interconnected by methine bridges, forming a stable macrocyclic structure.

• It features a central iron ion (Fe2+) which can coordinate with oxygen, enabling its function in various biological processes.

7. Functions of Heme

• Transport Functions:

  • Essential in transporting oxygen (O2) from the lungs to tissues and carbon dioxide (CO2) from tissues to the lungs.

• Sensor Functions:

  • Acts as a signaling molecule for nitric oxide (NO), playing roles in vascular function and immune responses.

• Electron Transport:

  • Integral component of cytochromes within the electron transport chain, facilitating ATP production during cellular respiration.

• Enzymatic Functions:

  • Acts as a cofactor for enzymes such as catalases and peroxidases, and is crucial in cytochrome P450 enzymatic reactions that detoxify drugs in the liver.

8. Heme and Related Molecules

• Heme is part of a family of vital molecules that include:

  • Chlorophyll: Mg2+ containing chlorin crucial for photosynthesis in plants.

  • Vitamin B12 (Cobalamin): Co2+ containing corrin essential for numerous metabolic pathways, especially in red blood cell formation.

  • Coenzyme F430: Ni2+ containing corphin involved in methane metabolism, assisting methanogenic bacteria.

  • Siroheme: Fe2+ containing isobacteriochlorin, important in biochemical processes like nitrite and sulfite reduction.

9. Structure/Function of Tetrapyrroles

Macrocyclic Structure:

• The large macrocyclic structure is adaptable for holding various metal ions essential for different biochemical functions.

• The oxidation state of the bound metal ion (such as Fe2+/Fe3+) plays a pivotal role in redox reactions.

• Role of Delocalized Electrons:

  • In photosynthesis, the delocalized electrons within the macrocycle contribute significantly to the molecule's ability to capture light energy.

10. Linear Tetrapyrroles: Bilanes

Characteristics of Bilanes:

• Linear tetrapyrroles, including bilirubin and biliverdin, serve as bile pigments with significant roles in the excretion of waste products from the breakdown of hemoglobin.

• In the plant kingdom, bilins are involved in capturing light energy during photosynthesis.

11. Next Steps

Preparation:

• Verify knowledge through the quiz on Moodle.

• Review the presentation providing detailed instructions on how to draw a tetrapyrrole, which aids in understanding its complex structure and function.