Metabolic

Heme derivatives play critical roles in oxygen transport, electron transfer, and detoxification. Understanding heme metabolism is essential for interpreting various clinical conditions

Heme Derivatives

Definition: Heme is a porphyrin ring complex with a central iron atom (usually in the Fe2+ ferrous state). It’s a prosthetic group essential for the function of various proteins
Examples
- Hemoglobin: Oxygen transport in red blood cells
- Myoglobin: Oxygen storage in muscle cells
- Cytochromes: Electron transport in mitochondria
- Catalase and Peroxidase: Detoxification of hydrogen peroxide
- Tryptophan Pyrrolase: Catalyzes the first step in the catabolism of tryptophan
Key Metabolic Pathways
- Heme Synthesis: Production of heme in the bone marrow and liver
- Heme Degradation: Breakdown of heme in the spleen and liver, leading to bilirubin formation

Heme Synthesis

Purpose: To produce heme, which is essential for hemoglobin, myoglobin, cytochromes, and other heme-containing proteins
Location: Bone marrow (primarily for hemoglobin synthesis) and liver (for cytochromes and other heme proteins)
Subcellular Location: Initial steps in mitochondria, intermediate steps in cytosol, and final steps back in mitochondria
Process
1. Glycine + Succinyl CoA → δ-Aminolevulinate (ALA)
  - Catalyzed by ALA synthase (rate-limiting enzyme) in mitochondria
  - Requires pyridoxal phosphate (vitamin B6) as a cofactor
2. 2 ALA → Porphobilinogen (PBG)
  - Catalyzed by ALA dehydratase (also known as porphobilinogen synthase) in the cytosol
  - Inhibited by lead
3. 4 PBG → Protoporphyrin
  - A series of enzymatic reactions in the cytosol convert four molecules of PBG into protoporphyrin
4. Protoporphyrin + Fe2+ → Heme
  - Catalyzed by ferrochelatase in mitochondria
  - Inhibited by lead
Regulation
- ALA synthase is the rate-limiting enzyme and is regulated by:
  - Heme: Inhibits ALA synthase (feedback inhibition)
  - Erythropoietin: Stimulates ALA synthase (in erythroid cells)
  - Drugs and Steroid Hormones: Can induce ALA synthase (in liver)

Heme Degradation

Purpose: To breakdown heme from aged or damaged red blood cells and recycle its components
Location: Primarily in the spleen and liver
Process
1. Heme → Biliverdin
  - Catalyzed by heme oxygenase in macrophages
  - Heme oxygenase opens the porphyrin ring, releasing iron (Fe2+) and carbon monoxide (CO)
2. Biliverdin → Bilirubin
  - Catalyzed by biliverdin reductase in macrophages
  - Bilirubin is insoluble in water (unconjugated bilirubin)
3. Bilirubin → Bilirubin-Albumin Complex
  - Bilirubin is transported in the blood bound to albumin
  - Albumin increases the solubility of bilirubin
4. Uptake by Liver
  - The bilirubin-albumin complex is taken up by hepatocytes
  - Bilirubin dissociates from albumin and is transported into the hepatocyte
5. Conjugation of Bilirubin
  - Bilirubin is conjugated with glucuronic acid by bilirubin UDP-glucuronosyltransferase (UGT) in the endoplasmic reticulum
  - Conjugation makes bilirubin water-soluble (conjugated bilirubin)
6. Secretion into Bile
  - Conjugated bilirubin is secreted into bile and transported to the small intestine
7. Conversion to Urobilinogen
  - In the intestine, bacteria convert conjugated bilirubin to urobilinogen
8. Fate of Urobilinogen
  - Most of the urobilinogen is excreted in the feces as stercobilin (gives feces its brown color)
  - A small amount of urobilinogen is reabsorbed into the blood and excreted in the urine as urobilin (gives urine its yellow color)

Iron Metabolism

Importance: Iron is a crucial component of heme and is tightly regulated
Dietary Iron: Absorbed in the small intestine
Transport: Transported in the blood bound to transferrin
Storage: Stored in cells as ferritin or hemosiderin
Regulation: Hepcidin, a hormone produced by the liver, regulates iron absorption and release

Porphyrias

Definition: A group of genetic disorders caused by deficiencies in enzymes of the heme synthesis pathway
Types: Different types are characterized by the specific enzyme deficiency
Symptoms: Vary depending on the type of porphyria
Diagnosis: Based on elevated levels of porphyrins and porphyrin precursors in urine, blood, and feces

Key Terms

Heme: A porphyrin ring complex with a central iron atom
ALA Synthase: The rate-limiting enzyme in heme synthesis
ALA Dehydratase: An enzyme in heme synthesis inhibited by lead
Ferrochelatase: An enzyme in heme synthesis that inserts iron into protoporphyrin, inhibited by lead
Heme Oxygenase: An enzyme that breaks down heme into biliverdin
Biliverdin Reductase: An enzyme that converts biliverdin to bilirubin
UDP-Glucuronosyltransferase (UGT): An enzyme that conjugates bilirubin with glucuronic acid
Urobilinogen: A product of bilirubin degradation in the intestine
Porphyrias: Genetic disorders caused by deficiencies in enzymes of the heme synthesis pathway
Hepcidin: A hormone that regulates iron absorption and release

Biochemicals

Physiology