WEEK 10 (Heme synthesis)

Question 1

Describe the structure of Heme

Answer 1

• A Fe-porphyrin compound
• Complex of PROTOPORPHYRIN IX and FERROUS IRON (Fe2+)
• Iron is held in the centre of the heme molecule by bonds to FOUR NITROGENS of the PORPHYRIN RING -> heme Fe2+ can form two additional bonds, one on each side of the planar porphyrin ring

Question 2

What is Haemoglobin?

Answer 2

An assembly of four globular protein subunits where each subunit is composed of a protein chain tightly associated with a non-protein heme group

Question 3

What are Porphyrins?

Answer 3

Cyclic compounds formed by fusion of 4 PYRROLE RINGS linked by METHENYL BRIDGES

Question 4

What are the major sites of heme biosynthesis?

Answer 4

• LIVER = synthesises a number of heme proteins
• BONE MARROW = active in Hb synthesis

Question 5

What is the difference in rate of heme synthesis in the liver and RBCs?

Answer 5

• LIVER = variable responding to alterations in the cellular heme pool caused by fluctuating demands for hemeproteins
• RBCs = relatively constant and is matched to the rate of global synthesis

Question 6

Describe the formation of Heme

Answer 6

1) δ-Aminolevulinic acid is formed from GLYCINE and SUCCINYL COA in a reaction catalysed by ALA SYNTHASE
2) Two molecules of δ-Aminolevulinic acid (ALA) condense to form PORPHOBILINOGEN by zinc-containing ALA DEHYDRATASE
[inhibition by heavy metal ions that replace zinc -> responsible for elevation in ALA and anemia seen in lead poisoning]
3) Four molecules of PORPHOBILINOGEN produces linear HYDROXYMETHYLBILANE by HYDROXYMETHYLBILANE SYNTHASE which is cyclised and isomerism by UROPROPHYRINOGEN III SYNTHASE to produce UROPROPHYRINOGEN
4) This is decarboxylated by UROPROPHYRINOGEN III DECARBOXYLASE to produce COPROPORPHYRINOGEN III
5) COPROPORPHYRINOGEN III enters the mitochondrion and two side chains are decarboxylated by COPROPORPHYRINOGEN III OXIDASE generating PROTOPORPHYRINOGEN IX which is oxidised to PROTOPORPHYRIN IX
6) Fe2+ is introduced to produce heme
[can occur spontaneously but is enhanced by FERROCHELATASE which is inhibited by lead]

Question 7

What are the two forms of ALA Synthase?

Answer 7

• ALA SYNTHASE 1 = found in all tissues
• ALA SYNTHASE 2 = found only in erythroid tissues

Question 8

What do Loss-of-function mutations in ALA Synthase 2 result in?

Answer 8

X-linked sideroblastic anemia and iron overload

Question 9

What are the properties of ALA synthase?

Answer 9

• Heme inhibits the synthesis of ALA synthesis (end-product inhibition)
• Allosterically inhibited by HEMATIN
• Lack of Vitamin B6 will decrease the synthesis of ALA

Question 10

What is Sideroblastic anemia?

Answer 10

A rare blood disorder that occurs when you have anemia from lack of red blood cells and too much iron in your system due to lack of iron use.

CAUSES:
- X-LINKED MUTATION IN ALA SYNTHASE
- VITAMIN B6 DEFICIENCY (inadequate dietary intake, chronic alcohol abuse, Isoniazid)

Heme synthesis impaired -> Increased Iron ->
- Cardiomyopathy
- Cirrhosis
- Enlarged spleen
- Kidney failure
- Diarrhoea

SYMPTOMS:
- Anemia
- Pallor
- Fatigability
- Dyspnea

DIAGNOSIS:
Microscopic examination of bone marrow aspiration and biopsy with PRUSSIAN BLUE STAIN -> Iron loaded mitochondria arranged around nucleus of Erythroblast

Question 11

How does lead poisoning affect Heme synthesis?

Answer 11

• Inhibition of FERROCHELATASE & ALA DEHYDRALATASE
• Displaces Zinc at enzyme active site

Question 12

What symptoms can Lead poisoning lead to in children?

Answer 12

• Developmental defects
• Drop in IQ
• Hyperactivity
• Insomnia

Question 13

What symptoms can Lead poisoning lead to in Adults?

Answer 13

• Severe abdominal pain
• Mental confusion

Question 14

What are Porphyrias?

Answer 14

Rare, inherited defects in heme synthesis resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors

Question 15

What can Porphyrins be classified into?

Answer 15

Erythropoietic or hepatic

Question 16

What can Hepatic Porphyrias be classified into?

Answer 16

Chronic or acute

Question 17

What can enzyme defects regarding tetrapyrroles result in?

Answer 17

• Enzyme defect prior to synthesis of tetrapyrroles = abdominal and neuropsychiatric signs
• Enzyme defect leading to accumulation of tetrapyrrole intermediates = photosensitivity

Question 18

Describe Acute Intermittent Porphyria (Hydroxymethylbilane synthase deficiency)

Answer 18

A late-onset autosomal dominant disease that is cause by Hydroxymethylbilane synthase deficiency

SYMPTOMS:
- Abdominal pain -> multiple laparoscopies
- Anxiety, paranoia and depression
- Paralysis
- Motor, sensory or autonomic neuropathy
- Weakness
- Excretion of ALA and PBG during episodes
- Dark port-wine coloured urine during standing

Some individuals are incorrectly diagnosed and placed in psychiatric institutions. Episodes can be induced by hormonal changes and drugs.

Question 19

Describe Porphyria Cutanea Tarda

Answer 19

An adult-onset hepatic porphyria in which hepatocytes are unable to decarboxylate UROPORPHYRINOGEN III in heme synthesis -> UROPORPHYRIN spills out of liver into the urine causing red-wine urine during standing -> Excessive alcohol or iron deposits can exacerbate the disease

FACTORS THAT CAN CAUSE IT:
- Hepatic iron overload
- Exposure to sunlight
- Hepatitis B or C

SYMPTOMS:
- Cutaneous rashes & blisters
- Urine that is red to brown in natural light or pink to red in UV light

TREATMENT:
- Treatment for pain and vomiting during acute porphyria attacks
- Severity diminished by intravenous injection of HEMIN and GLUCOSE -> decreases synthesis of ALA SYNTHASE 1
- Protection from sunlight
- Ingestion of B-CAROTENE
- PHLEBOTOMY -> porphyrias with photosensitivity