L1: Haem synthesis Flashcards
What are porphyrins?
are cyclic compounds synthesized in the human body
What do porphyrins form?
metalloporphyrins (Haem). “After conjugation with metals”
What is the result of the conjugation of heme with proteins?
Haemoproteins:
1) Haemoglobin of RBCs.
2) Myoglobin of muscle.
3) Cytochromes: Respiratory enzymes in the electron transport chain.
What contains FE-porphyrins as prosthetic “synthetic” groups?
Haemoproteins:
1) Haemoglobin of RBCs.
2) Myoglobin of muscle.
3) Cytochromes: Respiratory enzymes in the electron transport chain.
What is porphyrins chemistry?
- They are complex structures consisting of 4 pyrrole rings, united by “methylene” bridges.
- The nitrogen of 4 pyrrole rings can form complex with metallic ions such as Fe++
What are the sites of synthesis of heme?
- Porphyrins are synthesized partly in the mitochondria and partly in the cytosol of most body tissues except mature red blood cells (due to lack of mitochondria) mainly in:
Bone marrow (80%). “Site of formation of RBCs”
Liver (15%). “Many mitochondria, hemoproteins that detoxify”
What are the steps of the synthesis of heme?
Step 1: Synthesis of δ-Amino Levulinic Acid (δ-ALA) (Intramitochondrial)
Step 2: Formation of Porphobilinogen (PBG) (Cytosolic)
Step 3 & 4: Formation of Uroporphyrinogen (Cytosolic)
Step 5: Formation of Coproporphyrinogen: (Cytosolic)
Step 6-8: Formation of haem: (Intramitochondrial)
What are the events that happened in step one of heme synthesis?
Glycine and succinyl CoA condense to form ALA in a reaction catalyzed by ALA synthase.
What is the rate-controlling step in hepatic porphyrin biosynthesis?
Step 1
What are the events that happen in step two of heme synthesis?
Two molecules of ALA condense to form porphobilinogen (PBG) “first payroll ring compound” by ALA dehydratase. “Removal of h2o”
What is ala dehydratase sensitive to?
ALA dehydratase is extremely sensitive to inhibition by heavy metal ions.
What does lead poisoning lead to?
leads to the accumulation of ALA and anemia.
What are the events that happen in step three of haem synthesis?
Four molecules of porphobilinogens (PBG) are condensed together by PBG deaminase, producing the linear tetrapyrrole, hydroxymethylbilane.
What are the events that happen in step four of haem synthesis?
- Ring closure and isomerization of hydroxymethylbilane produce uroporphyrinogen III.
- This reaction is catalyzed by the enzyme uroporphyrinogen III synthase.
What are the events that happen in step five of heme synthesis?
Uroporphyrinogens undergo decarboxylation of their acetate groups, catalyzed by the enzyme uroporphyrinogen decarboxylase, generating coproporphyrinogens.
“Uro—->copro”
What are the events that take place in steps from No. 6 to number 8 in heme synthesis?
The 2 side chains of coproporphyrinogen are decarboxylated generating protoporphyrinogen IX. “Copro—>proto”
Proto-porphyrinogen IX is oxidized to proto-porphyrin IX.
The introduction of iron (as Fe+2) into proto-porphyrin IX occurs spontaneously, but the rate is enhanced by the ferrochelatase enzyme, which is inhibited by lead.
How is heme regulation Done?
The key regulatory enzyme is δ-ALA synthase (in mitochondria).
What are the regulatory influences and effects of inhibitors in heme synthesis
1) Effect of O2: haem synthesis is stimulated by low O2 tension (e.g. living at high altitudes). “Negative feedback”
2) Steroids: Stimulate δ-ALA synthetase.
3) Iron: Stimulate δ-ALA synthetase.
4) Lead: It is known to produce profound abnormalities in porphyrin metabolism. It inhibits δ-ALA synthetase, δ-ALA dehydratase “most sensitive” and haem synthetase.
“Stimulate—>ISO”
What is the definition of Porphyrias?
❖ Porphyrias are the metabolic disorders of heme synthesis, characterized by accumulation and increased excretion of porphyrins or their precursors.
What causes porphyrias?
❖ Porphyrias may be due to deficiency of one or more of heme biosynthesis enzymes → ↓ heme production → ↑ porphyrins.
❖ E.g.: uroporphyrin synthetase - uroporphyrin decarboxylase – coproporphyrin oxidase.
what are the types of porphyrias?
❖ Porphyrias are either congenital or acquired.
❖ Acquired porphyria may be due to intake of:
1) Sulfonamides (antibacterial).
2) Sulfonylureas (antidiabetic).
3) Barbiturates (anticonvulsant).
4) Antifungals e.g. griseofulvin.
❖ The most common acquired form of porphyria is due to lead poisoning. “Non-drug induced”
“Sulf sulf barb fungal”
What are the manifestations of porphyrias?
1) Abdominal pain.
2) Neuropsychiatric symptoms.
3) Photosensitivity: There are skin itches and burns (pruritis) when exposed to visible light
4) Porphyrinuria: Porphyrins are excreted in urine → dark urine.
What causes photosensitivity in porphyrias?
Due to the presence of increased amounts of uro-, copro-, protoporphyrins in tissues with strong absorption of light at 400 nm wavelength, associated with the release of energy and free radicals → tissue damage.
