Haem Synthesis & Porphyrias Flashcards
Name the haem containing compounds
- Hemoglobin
→ Found only in RBC
→ Composed of 4 polypeptide chains (2 alpha, 2 beta).
→ Each polypeptide chain has one haem group (total of 4) - Myoglobin
→ Found mainly in muscle tissue
→ Composed of a single polypeptide chain and has 1 haem group - Cytochromes
- Peroxidase
- Catalase
- Tryptophan pyrrolase 7. Nitric oxide synthase.
Show the ring structure of porphyrin present in haem
Haem is a complex of protoporphyrin IX and ferrous iron
The iron is held in the center of the haem molecule by bonds to the 4 nitrogens of the porphyrin ring
Porphyrin are cyclic compounds formed by fusion of 4 pyrrole rings linked by methenyl (=CH-) bridges
The pyrrole rings are numbered I to IV and the bridges are names as alpha to delta.
Mention the site and subcellular site of Haem synthesis
Site ⇒ Liver (major) and bone marrow (erythrocyte producing cells of the bone marrow)
Subcellular site ⇒ mitochondria and cytoplasm
Mature RBC lack mitochondria and are unable to synthesize haem
Explain the reactions of Haem synthesis in detail
Step 1 ⇒ Delta-ALA formation (in mitochondria)
- delta-Aminolevulinic acid
- Glycine + Succinyl CoA → delta ALA (condensation)
- Enzyme: ALA synthase
- Coenzymes: Pyridoxal Phosphate (B6, PLP)
- Byproducts: CoA + CO2
- The enzyme ALA synthase is the rate limiting enzyme of the pathway
Step 2 ⇒ Porphobilinogen formation (in cytoplasm)
- ALA + ALA → Porhopbilinogen (PBG) (condensation)
- Enzyme: ALA dehydratase
- Coenzyme: Zn2+
Step 3 ⇒ Uroporphyrinogen formation
- 4xPBG → Uroporhyrinogen (UPG-III) (first porphyrin ring) (Condensation)
- Enzyme: Uroporhyrinogen III synthase
Step 3b ⇒ Formation of CPG-III
- coproporhyrinogen
- UPG-III → CPG-III (decarboxylation)
- Enzyme: Uroporphyrinogen decarboxylase
Step 4: Haem formation (CPG-III enters back into the mitochondria)
- Two prpopionate side chains are decarboxylated (by CPG-III oxidase) to vinyl groups
→ This makes protophyrinogen IX → oxidized protoporphyrin IX
Enzyme: Ferrochelotase. Helps with attachment of ferrous iron to the protoporphyrin → generating haem.
- Haem is red
- Once the ferrous iron in haem gets oxidized to ferric form, hemin (hematin) is formed.
- Hemin is dark brown, which loses the property of carrying the oxygen
Explain the regulation of Haem synthesis in detail
Haem production in liver for hemoproteins like CyP450 (detoxifier) and erythroid cells (Haemoglobin synthesis)
Regulation in the liver:
1. Haem and hemin control the activity of ALAS1 (ALA synthase 1, in first step of haem synthesis). ALAS1 is a key regulatory enzyme
2. When the porphyrin production exceeds the availability of the apoproteins thta require it, haem accumulates and is converted to hemin. Via oxidation of Fe2+ → Fe3+.
3. Hemin decreases the amount of activity of ALAS1
Effect of Drugs on ALAS1:
1. Administration of large amount of drugs results in significant increase in hepatic ALAS1 activity (phenovarbital, insecticides)
2. Drugs that are metabiolized by CYP (hemeprotein oxidase system in the liver)
3. In response, there is an increase in CYP synthesis → therefore enhanced consumption of haem.
4. As a result, three is a decrease in concentraiton of haem in the liver cells
5. Low IC [Haem] → an increase in the synthesis of ALAS1 (induction)
Regulation of haem biosynthesis
1. ALAS does not appear to control the haem synthesis in the erythroid cells
2. Uroporphyrinogen synthase and ferrochelatase mostly regulate haem formation in these cells.
The effect of lead poisoning
Lead (Pb) intoxication disturbs biosynthesis
- Lead interacts with Zn2+ cofactor for ALA dehydratase (Step 2) and ferrochelatase (Step 4)
- Leads to inhibition of these two enzymes
- Leads to ALA and some protoporphyrin IX accumulating in urine
Symptoms → Abdominal pain, vomiting, fatigue, irritability and developmental disability in children
What are porphyrias?
Group of rare genetic disorders which result from a deficiency of enzymes in haem biosynthesis
Effects:
1. Increased secretion of porphyrins or porphyrin precurosrs
2. Affects the Nervous system and the skin
Most porphyrias are inherited as autosomal dominant traits
What is the classificaiton of porphyrias?
Erythropoeitic or Hepatic, depending on the location of the defectgive enzyme in BM or liver
Hepatic porphyrias
1. Acute ⇒ Acute intermittent porphyria (AIP) (i.b PBG → UPG)
2. Chronic ⇒ Porphyria cutanea tarda (i.b UPG → CPG)
Eryhtropoeitic porphyrias
1. Congenital eryhtropoietic porphyria (i.b PBG → UPG)
2. Hereditary protoporphyria (i.b CPG → PPG)
Relate the defects with clinical features and biochemical findings in acute intermittent porphyria.
Inherited as an autosomal dominant trait
Enzyme defect ⇒ PBG-deaminase (UPG-I synthase)
Occurence:
→ Most severe hepatic form of porphyria and more common in women
→ Women have less severe manifestations before menarche and after menopause, therefore female sex hormones have stimulatory effect on ALA synthase
Biochemical findings:
1. Enzyme defect leading to the accumulation of Porphobilinogen and ALA in the urine and blood
2. No discoloration of urine (darks on exposure to air due to photo-oxidation of PBG to porphobilin). Urine samples for PBG should be collected and transported in dark bottles
3. Porphyrins are not excreted in blood, so there is no photosenstivity.
Clinical Features:
1. Abdominal pain
2. Neuropsychiatric disturbances
3. Patients are not photosensitive
4. Symptoms are precipitated by use of drugs like barbiturates and ethanol.
Relate the defects with clinical features and biochemical findings in porphyria cutanea tarda (CBL)
Most common pophyria, and is a chronic disease of the liver.
Autosomal dominant
Enzyme defect ⇒ Uroporphyrinogen decarboxylase
Biochemical findings:
1. Large amounts of uroporphyrins build up in the liver and excreted in the urine.
2. Porphyrin accumulation leads to cutaneous symptoms and urine color is red to brownish.
Symptoms:
1. Patients are photosensitive (skin itches and burns when exposed to sunlght)
