Hemoglobin: Heme Synthesis and Degradation Study Notes，

Hemoglobin (Hb) is a protein located in red blood cells.
- Carries oxygen throughout the body.
- Responsible for the red color of blood.

Quaternary Structure of Protein
- Composed of more than one subunit, specifically two types of chains: alpha (α) and beta (β).
Components:
- α Chain: 2 polypeptide chains.
- β Chain: 2 polypeptide chains.
- Heme Group: Each polypeptide chain contains one heme group, which includes iron (Fe²⁺).

Measured in grams per deciliter (g/dl).
Normal Levels:
- Males: 14 to 18 g/dl
- Females: 12 to 16 g/dl
Health Conditions Related to Hemoglobin Levels:
- Low levels can lead to anemia.
- High levels can result in erythrocytosis, a condition characterized by an excess of red blood cells.

Transport of Respiratory Gases:
- Oxygen Transport: Carries oxygen from lungs to tissues.
- Carbon Dioxide Transport: Transports carbon dioxide from tissues back to the lungs.
Gas Exchange Mechanism:
- Hemoglobin undergoes a change in shape, facilitating the release of oxygen from the heme complex into the tissues.

Heme Composition:
- Composed of porphyrin ring and Fe²⁺ (iron).
Iron Function: Reversibly binds oxygen, which is crucial for the transport of oxygen in the bloodstream.

Heme Structure:
- Consists of a tetrapyrrole ring formed by four pyrrole rings.
- Each pyrrole ring includes four carbon atoms and one nitrogen atom.
Porphyrins:
- These are complex organic compounds featuring four pyrrole rings linked by methine bridges.
- Capable of hosting an iron atom, essential for oxygen binding.

Location: Heme synthesis occurs in the cytosol and mitochondria of liver and bone marrow cells.
Key Precursors: Succinyl-CoA and Glycine are the starting materials.

Initial Reaction:
- Condensation of succinyl CoA and glycine by ALA synthase leads to 5-aminolevulinic acid (ALA).
- ALA is transported to the cytoplasm.
Formation of Porphobilinogen:
- Two molecules of ALA combine to form Porphobilinogen (PBG) with the help of ALA Dehydratase.
Formation of Hydroxymethylbilane:
- Four Porphobilinogen molecules join to form linear tetrapyrrole called hydroxymethylbilane, facilitated by PBG Deaminase.
Cyclization:
- Hydroxymethylbilane cyclizes to uroporphyrinogen III (UPG), a heme precursor, via UPG III synthase.
Decarboxylation:
- Acetyl groups of UPG are converted into methyl groups to generate Coproporphyrinogen III (CPG) by UPG decarboxylase.
Return to Mitochondria:
- CPG is transported back to the mitochondrion for further transformation.
Conversion to Protoporphyrinogen IX:
- CPG is oxidized by Coproporphyrinogen oxidase, becoming Protoporphyrinogen IX.
Formation of Protoporphyrin IX:
- Conversion of Protoporphyrinogen IX into Protoporphyrin IX occurs through protoporphyrinogen oxidase.
Heme Formation:
- Protoporphyrin IX combines with iron (Fe²⁺) in the presence of ferrochelatase to produce heme.

Red Blood Cell Lifespan: Normal lifespan is approximately 120 days.
Phagocytosis: Senescent red blood cells are phagocytosed by macrophages,
- Typically in the spleen, liver, or reticuloendothelial system (extravascular lysis).

Globin: Hydrolyzed into free amino acids.
Heme: Decomposed into:
- Biliverdin
- Iron (Fe): Recycled or stored by the body.

Solubility: Bilirubin is initially water-insoluble but must be conjugated in the liver for excretion.
Production Sources:
- ~80% from degradation of hemoglobin in aged red blood cells.
- ~20% from breakdown of other heme-containing proteins (e.g. myoglobin).

Direct Bilirubin: Conjugated (water-soluble).
Indirect Bilirubin: Unconjugated (water-insoluble).
Total Bilirubin Calculation:
- Total Bilirubin = Conjugated + Unconjugated Bilirubin.

Production: Heme degradation to produce unconjugated bilirubin.
Transport in Plasma: Unconjugated bilirubin binds to albumin for transport.
Hepatic Phase:
- Uptake by hepatic cells.
- Conjugation with glucuronic acid to form bilirubin-glucuronides.
- Excretion into bile ducts.
Intestinal Delivery: Bile containing conjugated bilirubin reaches the intestine and is ultimately excreted.

In the gut:
- Bilirubin is converted to urobilinogen by gut bacteria.
- 80% of urobilinogen is transformed into stercobilin for fecal excretion.
- 18% enters enterohepatic circulation.
- 2% converts into urobilin and is excreted in urine.

Definition: Jaundice is characterized by yellow discoloration of skin/eyes caused by excess bilirubin in the blood.
Normal Plasma Concentration: Total bilirubin levels of 0.3 - 1.2 mg/dl.
- Jaundice appears when levels exceed 2 - 2.5 mg/dl.

Pre-Hepatic (Hemolytic Jaundice):
- Caused by increased hemolysis.
- High levels of unconjugated bilirubin.
Hepatic (Hepatocellular Jaundice):
- Occurs with liver damage impairing bilirubin uptake and conjugation.
- Both direct and indirect bilirubin may rise.
Post-Hepatic (Obstructive Jaundice):
- Arises from bile duct obstruction.
- Increased conjugated bilirubin in serum and dark urine.

Varied causes across classifications, such as:
- Pre-hepatic: Hemolysis, autoimmune conditions, sickle cell disease.
- Hepatic: Viral hepatitis, liver cirrhosis.
- Post-hepatic: Gallstones, pancreatic cancer.

Common in newborns; associated with immature liver enzyme function.
- Characterized by elevation of unconjugated bilirubin.
Treatment: Phototherapy is used to convert bilirubin into more water-soluble forms for easier excretion.

Upon completion, students should be able to summarize the functions of hemoglobin, including its synthesis and breakdown processes.