Flashcards in Quiz 4: Hemoglobin Synthesis Deck (18)
Substances needed for Hgb synthesis and breakdown
1. Porphyrins: Needed to make Heme
2. Hemoglobin: Needed for Oxygen transport
3. Iron transport and binding: Needed for Heme and Oxygen
• Precursors to Heme
• Can chelate metals, forms compounds that can participate in oxygen saturation and oxygen release
• Chemical intermediates in the synthesis of Hemoglobin (Hgb), Myoglobin, cytochromes, and enzymes
Iron in Porphyrins and Heme
• Iron is chelated within porphyrin to make heme, then bound to protein (hemoglobin and myoglobin)
• Heme molecule chelates Fe which is used to store and release oxygen.
• The synthesis of hemoglobin (Hb) is performed by 8 different enzymes.
• Synthesis begins with the condensation of ALA into PBG.
Heme Synthesis Regulation
Rate of heme synthesis is regulated by ALA
If Hemoglobin drops (i.e. anemia), ALA increases.
In bone marrow, rate of heme synthesis is under control of cellular iron uptake, erythrocyte production and other enzymes
Severe abdominal pain, vomiting, paralysis, psychiatric disorder
• Neuropsychiatric symptoms: excess in early precursors, ALA, ALADehydrogenase
• Cutaneous symptoms: exess with later porphyrin products (URO, COPRO, PROTO); photosensitivity due to absorption of light by porphyrins
Acute porphyria, Cutaneous porphyria
• Overproduction of heme precursors either in bone marrow (erythropoietic) or in liver.
• There can be enzyme deficiency at every stage of heme synthesis
• Inherited (autosomal dominant trait) or Acquired (lead exposure - cause increased urinary porphyria)
• “attacks”- due to exposure to precipitating conditions such as sunlight, drugs
• abnormal hair growth, photosensitivity, discolored urine, stomach pain, vomiting, fever, liver complications
• Specimen type may be serum, urine or feces
• Distinguish which porphyrin is in excess
• Rare – AIP (Scandinavian descent), ADP
• Most common disorders are:
PCT: deficiency of UPRO decaroboxylase
EPP: deficiency of ferrochelatase, last enzyme in heme pathway.
Laboratory Porphyrin Testing
• Tests are based on the enhanced fluorescence of these compounds in acidic solution
• Screening tests for urinary PBG:
- Watson-Schwartz test:
PBG (porphobilinogen) + Erlich’s reagent (acidic p- dimethylaminobenzal dehyde), positive is Cherry Red - chloroform can be added to separate PBG from interfering compounds
- Molecular Diagnostics: testing for genes that encode enzymes for heme synthesis
• Four heme groups introduced into each molecule of hemoglobin.
• Heme is the porphyrin ring with iron chelated in center.
• Protein portion is globulin chains
Normal Hemoglobin Structure
• Hemoglobin A or A1
• 2 alpha + 2 beta chains
• 3% of normal Hgb can be A2 (2 alpha + 2 delta chains)
• Hgb F: 2 alpha + 2 gamma chains; normal in fetal life, gradually shifts to beta chains by 9months old.
Types of Hemoglobinopathies
Four groups of abnormalities:
- Amino acid substitutions: Hgb S, C, D, E, O, G
- Amino acid deletion
- Elongated globulin chains
- Fused or hybrid chains
• Defects in production of normal Hgb molecules, rate and production of Hgb
• Inherited: homo or heterogenous
• Alpha Thalassemia: alpha globin chain is missing or reduced
• Beta Thalassemis: beta chain is affected
- Occurs in immature RBC in bone marrow (nucleated RBC, reticulocytes)
- Made in mitochondria
- Fe is transported to developing RBC by transferrin and transverses through the cell membrane to mitochrondria and inserted into PROTO ring to form Heme
- Protein synthesis of globulin changes occurs in cytoplasmic polyribosomes
1. Degradation of Hemoglobin
2. Removal and recycle of iron.
3. Removal and digestion of protein, which is returned amino acids pool.
4. Conversion of tetrapyrrole ring to bilirubin within the liver.