L1: Haem synthesis

Question 1

What are porphyrins?

Answer 1

are cyclic compounds synthesized in the human body

Question 2

What do porphyrins form?

Answer 2

metalloporphyrins (Haem). “After conjugation with metals”

Question 3

What is the result of the conjugation of heme with proteins?

Answer 3

Haemoproteins:

1) Haemoglobin of RBCs.
2) Myoglobin of muscle.
3) Cytochromes: Respiratory enzymes in the electron transport chain.

Question 4

What contains FE-porphyrins as prosthetic “synthetic” groups?

Answer 4

Haemoproteins:

1) Haemoglobin of RBCs.
2) Myoglobin of muscle.
3) Cytochromes: Respiratory enzymes in the electron transport chain.

Question 5

What is porphyrins chemistry?

Answer 5

• 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++

Question 6

What are the sites of synthesis of heme?

Answer 6

• 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”

Question 7

What are the steps of the synthesis of heme?

Answer 7

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)

Question 8

What are the events that happened in step one of heme synthesis?

Answer 8

Glycine and succinyl CoA condense to form ALA in a reaction catalyzed by ALA synthase.

Question 9

What is the rate-controlling step in hepatic porphyrin biosynthesis?

Answer 9

Step 1

Question 10

What are the events that happen in step two of heme synthesis?

Answer 10

Two molecules of ALA condense to form porphobilinogen (PBG) “first payroll ring compound” by ALA dehydratase. “Removal of h2o”

Question 11

What is ala dehydratase sensitive to?

Answer 11

ALA dehydratase is extremely sensitive to inhibition by heavy metal ions.

Question 12

What does lead poisoning lead to?

Answer 12

leads to the accumulation of ALA and anemia.

Question 13

What are the events that happen in step three of haem synthesis?

Answer 13

Four molecules of porphobilinogens (PBG) are condensed together by PBG deaminase, producing the linear tetrapyrrole, hydroxymethylbilane.

Question 14

What are the events that happen in step four of haem synthesis?

Answer 14

• Ring closure and isomerization of hydroxymethylbilane produce uroporphyrinogen III.
• This reaction is catalyzed by the enzyme uroporphyrinogen III synthase.

Question 15

What are the events that happen in step five of heme synthesis?

Answer 15

Uroporphyrinogens undergo decarboxylation of their acetate groups, catalyzed by the enzyme uroporphyrinogen decarboxylase, generating coproporphyrinogens.

“Uro—->copro”

Question 16

What are the events that take place in steps from No. 6 to number 8 in heme synthesis?

Answer 16

 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.

Question 17

How is heme regulation Done?

Answer 17

The key regulatory enzyme is δ-ALA synthase (in mitochondria).

Question 18

What are the regulatory influences and effects of inhibitors in heme synthesis

Answer 18

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”

Question 19

What is the definition of Porphyrias?

Answer 19

❖ Porphyrias are the metabolic disorders of heme synthesis, characterized by accumulation and increased excretion of porphyrins or their precursors.

Question 20

What causes porphyrias?

Answer 20

❖ 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.

Question 21

what are the types of porphyrias?

Answer 21

❖ 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”

Question 22

What are the manifestations of porphyrias?

Answer 22

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.

Question 23

What causes photosensitivity in porphyrias?

Answer 23

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.