Heme And Porphyrin Synthesis

Question 1

Which of the following is the main rate-limiting enzyme for the synthesis of haem in the
hepatocytes?
A. Uroporphyrinogen synthase I
B. Delta-aminolevulinic acid synthase 2
C. Uroporphyrinogen synthase III
D. Delta-aminolevulinic acid synthase 1.

Answer 1

Correct Answer: D. Delta-aminolevulinic acid synthase 1 (ALAS1)

Explanation:
• ALAS1 is the rate-limiting enzyme for heme synthesis in hepatocytes (liver cells).
• It catalyzes the first step: combining glycine and succinyl-CoA to form delta-aminolevulinic acid (ALA).
• It is regulated by heme through feedback inhibition.

Why the others are incorrect:
• A. Uroporphyrinogen synthase I:
Not a rate-limiting step. It is involved later in the pathway.
• B. Delta-aminolevulinic acid synthase 2 (ALAS2):
This is the erythroid (bone marrow) isoform, not the one used in hepatocytes.
• C. Uroporphyrinogen synthase III:
Also involved later in the pathway, not the rate-limiting enzyme.

In summary:
• Liver cells → ALAS1 (option D)
• Bone marrow → ALAS2

Question 2

A patient presents to the emergency room with abdominal pains, vomiting, weakness and convulsions. Urine analysis showed elevated porphobilogen and aminolevulinic acid. Which enzyme in the haem synthesis pathway is likely to be deficient?
A. Porphobilinogen deaminase..
B. Uroporphrinogen III synthase.
C. Aminolevulinic acid synthase.
D. Ferrocheletase.

Answer 2

A patient presents with abdominal pain, vomiting, weakness, convulsions, and elevated porphobilinogen and ALA. Which enzyme is likely deficient?

Correct answer: A. Porphobilinogen deaminase

Explanation:
This is classic acute intermittent porphyria (AIP).
• It shows up with neurological symptoms and elevated ALA + porphobilinogen.
• The defective enzyme is porphobilinogen deaminase.
• The others are involved later in the pathway or give different symptoms (like skin issues).

Great question! Let’s go back to Question 12 and explain why C may look tempting but A is the correct answer:

12. A patient presents to the emergency room with abdominal pain, vomiting, weakness, and convulsions. Urine analysis shows elevated porphobilinogen and aminolevulinic acid (ALA). Which enzyme in the haem synthesis pathway is likely to be deficient?
    • A. Porphobilinogen deaminase ← Correct
    • B. Uroporphyrinogen III synthase
    • C. Aminolevulinic acid synthase
    • D. Ferrochelatase

Why not C (ALA synthase)?

ALA synthase (ALAS) is the first enzyme in the heme synthesis pathway.
• If it were deficient, you would expect low ALA, not high ALA.
• The body wouldn’t even make ALA in the first place.

Why A is correct:

The patient has:
• Abdominal pain, vomiting, and neuro symptoms → classic signs of Acute Intermittent Porphyria (AIP).
• Lab: Increased ALA and porphobilinogen (PBG).

In AIP, the enzyme porphobilinogen deaminase is deficient.
This leads to:
• Build-up of ALA and PBG (because the enzyme that uses PBG is not working).

Quick summary:

Enzyme Deficient Disease Key Lab Findings
ALA synthase Rare; not typical here ↓ ALA and PBG
PBG deaminase AIP ↑ ALA, ↑ PBG ← our case
Uroporphyrinogen III synthase CEP (Gunther disease) ↑ Uroporphyrin I, skin symptoms
Ferrochelatase Erythropoietic protoporphyria Photosensitivity

So, A is correct, not C. Let me know if you’d like a simple flowchart for heme synthesis disorders!

Question 3

How does heme synthesis occur?

Answer 3

Here’s a clear distinction between ALA synthase and ALA dehydratase to help you understand them better:

1. ALA Synthase (Aminolevulinic Acid Synthase)

Function:
• Catalyzes the first and rate-limiting step of heme synthesis:
Succinyl-CoA + Glycine → ALA (aminolevulinic acid)

Location:
• Mitochondria

Regulation:
• Inhibited by heme (via negative feedback)
• Induced by drugs like barbiturates and alcohol (they use heme for cytochrome P450)

Clinical relevance:
• Target of treatment in porphyrias (e.g., IV haemin suppresses ALA synthase)

2. ALA Dehydratase (also called Porphobilinogen Synthase)

Function:
• Catalyzes the second step of heme synthesis:
2 ALA → Porphobilinogen (PBG)

Location:
• Cytosol

Regulation:
• Inhibited by lead (this causes ALA buildup in lead poisoning)

Clinical relevance:
• Not the target of haemin treatment
• Deficiency leads to accumulation of ALA

Simple Mnemonic:
• ALA Synthase: Starts the pathway (S for Synthase, S for Start)
• ALA Dehydratase: Deals with ALA and converts it to PBG

Let me know if you want a visual or table for easier memorization.

Question 4

Question 43: At the isoelectric pH, the separation of amino acids is based on:

Correct Answer: C. Solubility

Why not A. Charge?
• At isoelectric point (pI), an amino acid has no net charge — it’s zwitterionic.
• Therefore, electrophoretic separation by charge (e.g., in paper or gel electrophoresis) won’t work effectively at the pI.
• So, charge-based separation is not useful at the isoelectric pH.

Why C. Solubility is correct:
• At the isoelectric point, amino acids have lowest solubility in water (since they can’t interact well with charged water molecules).
• Thus, solubility differences become the key factor for separation — especially in crystallization or precipitation techniques.

Now, techniques based on each option:
• A. Charge →
Technique: Electrophoresis (e.g., paper, gel, capillary) — works best away from pI, when amino acids have net charge.
• B. Osmolality →
Rarely used for separation of amino acids; more relevant in osmotic balance studies or dialysis fluids.
• C. Solubility →
Technique: Salting out, crystallization — important when working at or near the isoelectric point.
• D. Size →
Technique: Gel filtration chromatography (also called size-exclusion chromatography).

Question 5

Correct Answer: tRNAᵢ alignment with mRNA.

This process happens first in the sequence of translation events in prokaryotes.

Explanation of each option:
1. tRNAᵢ alignment with mRNA →
• This refers to initiator tRNA (fMet-tRNAᶠᴹᵉᵗ) pairing with the start codon (AUG) on the mRNA.
• It occurs right after the small ribosomal subunit binds to the mRNA.
• It is one of the first steps in translation initiation.
2. Recruitment of termination factors to the A site →
• Happens only during termination, when a stop codon is reached.
• So, it occurs much later.
3. Export of mRNA from the nucleus →
• Not applicable in prokaryotes, since they lack a nucleus.
• Transcription and translation occur simultaneously in the cytoplasm.
4. Movement of the ribosome from one codon to the next →
• This is part of elongation, and happens after initiation is complete.

Summary of prokaryotic translation initiation (in order):
1. mRNA binds to small ribosomal subunit via Shine-Dalgarno sequence.
2. Initiator tRNA (fMet-tRNAᶠᴹᵉᵗ) aligns with start codon.
3. Large ribosomal subunit joins to form full complex.
4. Translation begins — elongation starts.

So tRNAᵢ alignment with mRNA clearly comes first.

Question 6

Which of the following below indicates the correct order of chromosome constituents going from smallest to largest?
A. Chromatin fibril, nucleosome, histone octamer, chromosome loop
B. fibril, chromosome loop, histone octamer.
C. Nucleosome, histone octamer, chromosome loop, chromatin fibril.
D. Histone octamer, nucleosome, chromatin fibril, chromosome loop
46. Generally, porphyrias are inherited as autosomal dominant trait, EXCEPT - porphyria cutanea tarda.
A. variegate porphyria.
B. congenital erythropoietic porphyria.
C. acute intermittent porphyria
47. In the segment of a transcribed gene, the non-coding strand of DNA has the following sequence 5’- AGCTCACTG-3. What will be the corresponding sequence in the mRNA produced from this segment of the gene?
A. AGCTCACTG
B. AGCUCACUG C. UGCTCUCTG D. CAGUGAGCU
48. Elemental lead (Pb) inhibits these two (2) enzymes in the haem synthesis leading to sideroblastic anaemia.
A. Coproporphrinogen oxidase and uroporphrinogen decarboxylase
B. Aminolevulinic acid dehydratase and ferrocheletase.
C. Porphobilogen deaminase and protoporphyrin IX oxidase.
D. Aminolevulinic acid synthase and aminolevulinic dehydratase
49. The first messenger of a signalling pathway is a small hydrophobic molecule. It is MOST likely to
be a receptor.
A. Nuclear
B. ligand-gated.
C. G-protein coupled.
D. tyrosine kinase.
50. The property of water that makes it central to life and able to interact with various biomolecules is
A. hydrophobic interaction.
B. ionic bonding
C. covalent bonding.
D. hydrogen bonding.
51. Which of the following bonds remains intact in denaturation?
A. Hydrophobic interaction
B. Hydrogen bond.
C. lonic bond.
D. Peptide bond.
Nucleosome,
chromatin
52. In
A. rich in amino acids.
B. less soluble.
C. more soluble.
D. deficient in amino acids
sickle cell anaemia, the sickled haemoglobin is
53. The following enzymes in haem synthesis are in the mitochondrion, EXCЕРТ
A. protoporphyrin IX oxidase.
B. Ferrocheletase
C. porphobilnogen deaminase

Answer 6

Here are the correct answers with explanations for each question:

45. Which of the following indicates the correct order of chromosome constituents from smallest to largest?

Correct answer: D. Histone octamer, nucleosome, chromatin fibril, chromosome loop

Explanation:
• Histone octamer is the protein core (smallest).
• Nucleosome = histone octamer + DNA wrapped around it.
• Chromatin fibril = a chain of nucleosomes.
• Chromosome loop = loops of chromatin fibers, part of higher-order chromatin structure.

46. Generally, porphyrias are autosomal dominant EXCEPT –

Correct answer: B. Congenital erythropoietic porphyria

Explanation:
• Most porphyrias (e.g., AIP, variegate) are autosomal dominant.
• Congenital erythropoietic porphyria (CEP) is autosomal recessive.

47. mRNA sequence from non-coding strand 5’-AGCTCACTG-3’?

Correct answer: D. CAGUGAGCU

Explanation:
• mRNA is made complementary to the template strand, which is the coding strand’s complement.
• Non-coding strand: 5’-AGCTCACTG-3’
→ Template strand (3’-TCGAGTGAC-5’)
→ mRNA (5’-CAGUGAGCU-3’).

48. Lead inhibits which two enzymes in heme synthesis?

Correct answer: B. Aminolevulinic acid dehydratase and ferrocheletase

Explanation:
• Lead blocks:
• ALA dehydratase (cytoplasm)
• Ferrochelatase (mitochondria)
• This leads to sideroblastic anemia due to impaired heme production.

49. The first messenger is a small hydrophobic molecule. Most likely receptor?

Correct answer: A. Nuclear

Explanation:
• Small hydrophobic molecules (e.g., steroid hormones) can cross the membrane and bind nuclear receptors directly.

50. Property of water central to life?

Correct answer: D. Hydrogen bonding

Explanation:
• Water’s ability to form hydrogen bonds allows:
• High heat capacity
• Solvent capabilities
• Cohesion/adhesion
• Interaction with biomolecules

51. Which bond remains intact during denaturation?

Correct answer: D. Peptide bond

Explanation:
• Denaturation breaks non-covalent bonds (hydrogen, ionic, hydrophobic), but not the peptide bonds (which are covalent).

52. In sickle cell anemia, sickled hemoglobin is:

Correct answer: B. Less soluble

Explanation:
• HbS has valine instead of glutamic acid, which is hydrophobic, making HbS less soluble, especially under low O₂ → polymerizes → sickling.

53. Enzymes in heme synthesis located in the mitochondrion, EXCEPT –

Correct answer: C. Porphobilinogen deaminase

Explanation:
• Mitochondrial enzymes: ALA synthase, Protoporphyrin oxidase, Ferrochelatase.
• Porphobilinogen deaminase is in the cytoplasm.

Let me know if you want these summarized as flashcards!

Question 7

How does heme synthesis occur

Answer 7

Sure! Here’s a clear step-by-step overview of heme synthesis, including the key enzymes and locations:

1. Starting point: Succinyl-CoA + Glycine
   • Where? Mitochondria (in liver and bone marrow cells mostly)
   • Enzyme: Aminolevulinic acid (ALA) synthase
   • Reaction: Succinyl-CoA + Glycine → Aminolevulinic acid (ALA)
   • Rate-limiting step (regulated tightly, inhibited by heme)
2. Formation of Porphobilinogen (PBG)
   • Where? Cytoplasm
   • Enzyme: ALA dehydratase (also called PBG synthase)
   • Reaction: 2 ALA → Porphobilinogen (PBG)
3. Formation of Hydroxymethylbilane
   • Where? Cytoplasm
   • Enzyme: Porphobilinogen deaminase (also called hydroxymethylbilane synthase)
   • Reaction: 4 PBG → Hydroxymethylbilane (linear tetrapyrrole)
4. Formation of Uroporphyrinogen III
   • Where? Cytoplasm
   • Enzyme: Uroporphyrinogen III synthase
   • Reaction: Cyclization of hydroxymethylbilane → Uroporphyrinogen III (cyclic tetrapyrrole)
5. Conversion to Coproporphyrinogen III
   • Where? Cytoplasm
   • Enzyme: Uroporphyrinogen decarboxylase
   • Reaction: Uroporphyrinogen III → Coproporphyrinogen III (removes acetate groups)
6. Conversion to Protoporphyrinogen IX
   • Where? Mitochondria
   • Enzyme: Coproporphyrinogen oxidase
   • Reaction: Coproporphyrinogen III → Protoporphyrinogen IX
7. Formation of Protoporphyrin IX
   • Where? Mitochondria
   • Enzyme: Protoporphyrinogen oxidase
   • Reaction: Protoporphyrinogen IX → Protoporphyrin IX (oxidation to form the porphyrin ring)
8. Insertion of Iron to form Heme
   • Where? Mitochondria
   • Enzyme: Ferrochelatase
   • Reaction: Protoporphyrin IX + Fe²⁺ → Heme

Summary of Enzyme Locations and Key Points:

Step Enzyme Location Function
1 ALA synthase Mitochondria Succinyl-CoA + Gly → ALA
2 ALA dehydratase Cytoplasm 2 ALA → Porphobilinogen
3 Porphobilinogen deaminase Cytoplasm 4 PBG → Hydroxymethylbilane
4 Uroporphyrinogen III synthase Cytoplasm Cyclizes to Uroporphyrinogen III
5 Uroporphyrinogen decarboxylase Cytoplasm Uroporphyrinogen III → Coproporphyrinogen III
6 Coproporphyrinogen oxidase Mitochondria Coproporphyrinogen III → Protoporphyrinogen IX
7 Protoporphyrinogen oxidase Mitochondria Protoporphyrinogen IX → Protoporphyrin IX
8 Ferrochelatase Mitochondria Inserts Fe²⁺ into protoporphyrin IX to make heme

Regulation:
• ALA synthase is the rate-limiting enzyme, inhibited by heme (feedback inhibition).
• Defects in any enzymes cause different types of porphyrias (disorders of heme synthesis).

If you want, I can also help explain the clinical significance or detail any step further!