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Digestion And Metabolism > Heme Synthesis > Flashcards

Heme Synthesis Flashcards

1
Q

What amino acid is used in heme synthesized?

A

Glycine

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2
Q

All cells need…

A

Heme synthesis

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3
Q

What are the major sites of heme synthesis?

A

The major sites for heme synthesis are the bone marrow and the liver.

Bone marrow:
Hemoglobin synthesis
a. Synthesis in erythroblast and reticulocytes.
b. Iron availability regulates heme synthesis.
c. Heme stimulates Hb globin chain synthesis

Liver:
Variable CYP450 synthesis
a. Heme is needed as prosthetic group. 
b. Heme regulates heme synthesis.
c. Heme accumulation is not wanted
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4
Q

What are the parts of heme?

A

Heme
is ferrous protoporphyrin IX

  • 4 pyrrole rings (A-D) are linked via methenyl bridges.
    • Side chains of heme:
  • A: methyl, vinyl
  • B: methyl, vinyl
  • C: methyl, propionyl
  • D: propionyl, methyl

• Ring Dis asymmetry

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5
Q

Explain the concept of heme synthesis

A

Concept of heme synthesis in all cells:
Use the same building blocks.
Start and end in mitochondria.

All reactions are irreversible.
1. Succinyl CoA and glycine form d-aminolevulinic acid (ALA) in mitochondria.

  1. ALA leaves mitochondria and 2 ALAs form PBG in cytosol.
  2. Four porphobilinogens are aligned and deaminated to the linear HMB.
  3. Uroporphyrinogen III is formed by enzymatic ring closure of HMB.
  4. Coproporphyrinogen III is formed by decarboxylation of uroporphyrinogen III in cytosol and is transported into mitochondria.
  5. Double-bonds are changed to eventually form the red protoporphyrin IX.
  6. Insertion of ferrous iron into protoporphyrin IX leads to hem
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6
Q

What is the regulated step of heme synthesis?

A

The regulated step of heme synthesis is catalyzed by ALA synthase

Succinyl CoA and glycine are the substrates.

Glycine is decarboxylated to form ALA.
Pyridoxalphosphate (PLP) from vitamin B6 is needed as coenzyme.

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7
Q

How is ALA synthsse regulated?

A

ALA synthase is regulated at the level of enzyme synthesis

Different regulation in liver as opposed to bone marrow

  • Most cells contain the isoform ALAS1. Gene expression is stimulated at low heme concentration and is feedback inhibited by heme accumulation.
  • Erythrocyte precursor cells contain the isoform ALAS2.
  • Translation of ALAS2 mRNA takes place only at sufficient intracellular iron
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8
Q

Describe heme synthesis in liver is controlled by free heme

A

Heme synthesis in liver is controlled by free heme in the following manner:

  1. Inhibition of ALAS1 synthesis:
    High levels of unincorporated heme reduce ALAS1 transcription, translation and the transport of the enzyme from cytosol
    into mitochondria.
  2. Stimulation of ALAS1 synthesis:
    Low intracellular heme concentration stimulates transcription. Certain drugs which induce CYP 450 increase ALAS1 synthesis
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9
Q

What is the impact of erythropoietin ?

A

Erythropoietin is released by the kidney at low oxygen levels in tissues and leads to RBC and hemoglobin synthesis. In erythroblasts the iron uptake is stimulated and leads to iron dependent heme synthesis in erythroid cells

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10
Q

How is ALAS2 synthesis regulated in the bone marrow?

A

ALAS2 synthesis is regulated by intracellular iron and is not inhibited by heme. The mRNA of ALAS2 has a hairpin iron-response element (IRE) and is translated
only when iron is present

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11
Q

Describe heme synthesis in bone marrow

A
  1. Erythropoietin is released by the kidney at low oxygen levels in tissues and leads to RBC and hemoglobin synthesis. In erythroblasts the iron uptake is stimulated and leads to iron dependent heme synthesis in erythroid cells.
  2. ALAS2 synthesis is regulated by intracellular iron and is not inhibited by heme. The mRNA of ALAS2 has a hairpin iron-response element (IRE) and is translated
    only when iron is present.
  3. Free heme is wanted as it increases the expression of the hemoglobin a- and
    b-globin chain genes thus ensuring a balanced synthesis for hemoglobin.
  4. The gene for ALAS2 is on the X-chromosome. Deficiency leads to X-linked
    sideroblastic anemia
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12
Q

What is the function of ALA dehydrogenase and PBG deaminase?

A
  1. ALAdehydratase(PBGsynthase)uses2ALAsto form porphobilinogen. Zinc is needed as cofactor.
  2. PBG deaminase aligns and deaminates 4 porphobilinogens to form the linear hydroxymethylbilane (HMB).
  3. It is critical that the enzymatic ring closure of HMB forms the porphyrin III ring system and leads to an asymmetric pyrrole ring D
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13
Q

How can inhibition of heme synthesis lead to microcytuc anemia?

A

Inhibition of heme synthesis can lead to
microcytic anemia

  1. Deficiency of vitamin B6
    ALA synthase needs pyridoxal phosphate (PLP) as coenzyme.
    Heme synthesis cannot start efficiently without pyridoxal phosphate in all cells.

Note: Isoniazid used for tuberculosis treatment and some other medical drugs lead to PLP depletion. Vitamin B6 supplementation is needed.

  1. Lead poisoning
    ALA dehydratase and ferrochelatase need zinc as cofactor. The heavy metal lead interacts with zinc which results in less heme synthesis in all cells.

ALA and a small amount of protoporphyrin IX accumulate in blood and urine

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14
Q

What causes porphyrias?

A
  1. Caused by a specific enzyme deficiency (genetic or acquired).
  2. Can lead to accumulation of intermediates of heme synthesis in blood,
    various tissues and urine
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15
Q

What are the clinical features of porphyrias?

A
  1. Clinical features:
    a. Severe abdominal pain, neurologic dysfunction and mental disturbance (AIP).
    b. Photosensitivity of the skin (PCT and very severe in CEP).
  2. Are often grouped into hepatic or erythropoietic porphyrias.
  3. Hepatic porphyrias:
    a. Treatment with intravenous glucose or hemin and saline.
    A metabolite of glucose inhibits ALAS1 whereas hypoglycemia induces heme synthesis. Hemin contains ferric iron and acts similar to heme.
    b. Symptoms worsened by drugs that induce hepatic Cytochrome P45
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16
Q

Enzyme deficiencies after formation of HMB…

A

Enzyme deficiencies after formation of HMB lead to skin photosensitive patients resulting from abnormal porphyrins.

17
Q

What is acute intermittent porphyria?

A

Severe deficiency of PBG deaminase (less than 50% activity)

More than 300 mutations of the hepatic PBG deaminase gene leading to. up-regulation of hepatic ALAS1.

ALA accumulates as the synthesis of ALAS1 is stimulated by low hepatic heme level.

Porphobilinogen accumulates as it is not used for HMB synthesis.

18
Q

Describe the clinical features and detection of AIP

A

Very severe abdominal pain, abdominal colic and severe constipation.
Weakness of the lower extremities. Systemic arterial hypertension.
Highly agitated state and mental disturbance. Tachycardia and respiratory problems. Patients are not photosensitive as HMB and abnormal porphyrins cannot be formed.

19
Q

Describe the detection of AIP

A

Detection:
Urine analysis by rapid dipstick method for porphobilinogen. Laboratory tests for ALA and porphobilinogen.

Urine color change: Porphobilinogen (colorless) is changed in urine after contact with air or light to the red purple-black porphobilin

20
Q

Explain AIP onset and treatment

A
  1. Onset of AIP can occur in patients who are treated with specific drugs which stimulate heme synthesis. AIP can also be triggered by infections, ethanol abuse or estrogen hormone therapy. AIP occurs in all races but is more common in Caucasians. It occurs predominantly in women (2nd to 4th decade).
  2. Treatment is immediate for pain and vomiting. The severity of acute symptoms can be diminished by saline and IV glucose or hemin. A glucose metabolite and hemin reduce ALAS1 gene expression whereas hypoglycemia induces ALAS1.
  3. Physicians shall not prescribe barbiturates or drugs that stimulate cytochrome P450 synthesis. This recommendation applies to treatment of hepatic porphyrias in general but it is absolutely critical in patients with AIP.
  4. Barbiturates lead to toxic ALA levels in AIP patients and can lead to death. ALA has a structure similar to GABA and competes with the binding to the GABA receptor
21
Q

What is Congenital Erythropoietic Poryphria?

A

Hereditary defect only in bone marrow

Deficiency of the erythroid isozyme of uroporphyrinogen III synthase leads to abnormal porphyrins and severe skin photosensitivity.

Genetic defect: autosomal recessive trait.
All other porphyrias are autosomal dominant trait

22
Q

Describe CEP type 1

A

CEP: accumulation of 2 porphyrins type I

Deficiency of erythroid uroporphyrinogen III synthase

HMB is spontaneously used to form the abnormal porphyrin ring Type I —> Upophyrinogen I—> Coproporhyrin I

Both of the last two will imcresse/accumulate

23
Q

Descrbe the most severe skin photosensitivity in CEP

A
  • It is critical that the ring closure of HMB is enzymatically performed which generates uroporphyrinogen III.
  • Erythroid uroporphyrinogen III synthase is deficient in CEP and the linear HMB spontaneously forms the abnormal porphyrin I ring. Uroporphyrinogen I is then decarboxylated to coproporphyrinogen I.
  • Both abnormal porphyrinogens type I lead to the red colored uroporphyrin I and coproporphyrin I which accumulate in blood, skin and tissue. This leads to extremely severe and painful photosensitivity caused by ROS formation in the skin.
  • The urine is red upon release
24
Q

What is the clinical feature of CEP?

A
  • ROS damage leads to poor wound healing, severe blisters and ulcers.
  • The teeth can be reddish-brown.
  • Hypertrichosis is often severe in CEP with werewolf features, hairy face and arms
25
Q

Explain CEP onset and treatment

A
  1. Onset occurs mainly in childhood or earlier caused by a hereditary defect of the erythroid-cell specific isozyme of uroporphyrinogen III synthase.
  2. CEP patients have severe pain when their skin comes into contact with UV light as the abnormal porphyrins are not included into proteins. This leads to ROS formation in the blood of skin vessels causing severe damage with blisters, poor wound healing and ulcers.
  3. Hemin IV treatment is not effective as ALAS2 gene expression is not inhibited by heme. Bone marrow transplantation is a possible treatment or hopefully other methods will be found
26
Q

What is Porphyria Cutanea Tarda (PCT)?

A

Common is photosensitivity with cutaneous lesions caused by uroporphyrin III accumulation in liver, blood and skin.

Deficiency of uroporphyrinogen III Decarboxylase

Upoporphyrin III accumulates

The urine is red upon release in natural light or pink in fluorescent light

27
Q

Describe porphyria cutanea tarda onset and treatment

A
  1. Onset occurs typically between 40-50 years of age.
  2. PCT Type I (80%) is acquired due to chronic disease of the liver such as hepatitis or ethanol abuse. PCT Type II is familial.
  3. The clinical expression is influenced by:
    a. Hepatic iron overload.
    b. Exposure to sunlight.
    c. Excessive alcohol ingestion.
  4. Treatment can include avoidance of: Sunlight and alcohol and reduction of dietary iron uptak
28
Q

What is the vitamin B6 deficiency impact on hene synthesis?

A

Vitamin B6 deficiency:
Deficiency of ALA synthase which needs PLP synthesized from B6. Can be caused by dietary deficiency but also by drug treatment

29
Q

What is the impact of lead poisoning to heme synthesis?

A

Lead poisoning:
Deficiency of ALA dehydratase and ferrochelatase. Accumulation of ALA and a small amount of protoporphyrin IX in blood and urine

30
Q

How does acute intermittent porphyria affect hene synthesis?

A

Acute Intermittent Porphyria (triggered):
Deficiency of PBG deaminase (HMB synthase).
Accumulation of ALA and porphobilinogen in blood and urine

31
Q

What enzyme deficiencies not leading to photisensitive patients?

A

Vitamin B6 deficiency

Lead poisoning

Acute intermittent porphyria

32
Q

What defects in heme synthesis lead to skin photosensitivity?

A

Concept: Defects of heme synthesis after formation of HMB
lead to skin photosensitivity of patients due to abnormal porphyrins.

The skin itches and burns when it is exposed to light (ROS formation) due
to abnormal porphyrins which are not incorporated into proteins.

  1. Congenital Erythropoietic Porphyria (CEP):
    Deficiency of erythroid uroporphyrinogen III synthase.
    Most severe photosensitivity. Blood, tissue, skin and urine show accumulation of uroporphyrin I & coproporphyrin I.
  2. Porphyria Cutanea Tarda (PCT):
    Deficiency of uroporphyrinogen decarboxylase.
    Accumulation of uroporphyrin III in blood, tissue, skin and urine

Digestion And Metabolism (57 decks)

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