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Medical Biochemistry and Genetics > Lecture 7 - Diseases of Heme Synthesis and Degradation > Flashcards

Lecture 7 - Diseases of Heme Synthesis and Degradation Flashcards

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USMLE® Step 1 flashcards Biology 101 flashcards
1
Q

What is the function of this hemoprotein: Hemoglobin?

A

Binding and transport of O2

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2
Q

What is the function of this hemoprotein: Myoglobin?

A

Binding and storage of O2

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3
Q

What is the function of this hemoprotein: Catalase?

A

Breakdown of H2O2

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4
Q

What is the function of this hemoprotein: Cytochrome b?

A

Electron transport

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5
Q

What is the function of this hemoprotein: Cytochrome P450?

A

Hydroxylation - detoxifies drugs and chemicals in our diet

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6
Q

What is the function of this hemoprotein: NO synthase?

A

Synthesis of nitric oxide (2nd messenger)

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7
Q

What is the function of this hemoprotein: COX-1 and COX-2? (cyclooxygenase)

A

Prostaglandin biosynthesis

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8
Q

What order is the order of the side chains on the pyrrole rings of heme?

A

*4 pyrrole rings linked by methenyl bridges
*conjugated double bonds –> color
In order from left to right:
I - Methyl, vinyl
II - methyl, vinyl
III - methyl, proprionyl
IV - propionyl, methyl

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9
Q

1) Where does heme synthesis take place?

2) Name diseases associated with this process

A

1) 200-300 mg/day is produced (small amount is absorbed from the gut)
- 80% in bone marrow (Hb)
- 15% in liver (cytochrome P450)

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10
Q

1) Where does heme degradation take place?

2) Name disease associated with this process

A

1) 200-300 mg/day is degraded
- Largely in spleen macrophages > liver, intestine and kidney
2) Jaundice (icterus)

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11
Q

If a term ends in “-in” ….

A

It will probably be colored (i.e. bilirubin) linked by -CH=

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12
Q

If a term ends in “-ogen” …

A

It will probably be colorless (i.e. phorphobilinogen) linked by -CH2-

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13
Q

Which steps of heme synthesis occur in the mitochondria and which steps occur in the cytoplasm?

A

Steps 1, 6, 7 and 8 occur in the mitochondria with the remainder occurring in the cytoplasm

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14
Q

Name the steps of heme synthesis

A

(Mitochondria) 1. Succinyl-CoA + Glycine –> (delta-aminolevulinic acid synthase aka ALAS) delta-aminolevulinic acid (ALA) + CoA + CO2
(Cytosol)
2. ALA –> (delta-aminolevulinic acid dehydratase) porphobilinogen
3. Porphobilinogen –> (Porphobilinogen deaminase/HMB synthase) Hydroxymethybilane (HMB) linear tetrapyrrole intermediate + NH3
4. HMB undergoes cyclization –> (Uroporphyrinogen III synthase) Uroporphyrinogen III
5. Uroporphyrinogen III –> (Uroporphyrinogen III decarboxylase) Coproporphyrinogen III
(Mitochondria)
6. Coproporphyrinogen III –> (Coproporphyrinogen III oxidase) Protoporphyrinogen IX
7. Protoporphyrinogen IX –> (Protoporphyrinogen IX oxidase) Protoporphyrin IX
8. Protoporphyrin IX + Fe2+ –> (Ferrochelatase) Heme

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15
Q

What is the first step of heme synthesis?

A

Succinyl-CoA + Glycine –> (delta-aminolevulinic acid synthase aka ALAS) delta-aminolevulinic acid (ALA) + CoA + CO2
*It also is the rate-limited step and is regulated

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16
Q

Name the isoforms of delta-aminolevulinic acid synthase (ALAS)

A
  • ALAS requires vitamin B6, pyridoxal phosphate
  • ALAS1 - “housekeeping” gene, located in all cells and is feedback inhibited by its end product heme (low heme levels can increase porphyria severity; hemin therapy)
  • ALAS2 - X linked gene located in erythroid cells (fetal liver, bone marrow), whose synthesis is stimulated by iron (derepression via IRE-BP)
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17
Q

What causes microcytic hypochromic (sideroblastic) anemia?

A

*Dietary deficiency disease of vitamin B6 or pyridoxal phosphate, characterized by RBCs which are smaller in size and have decreased red color

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18
Q

Name genetic disorders of ALAS2

A

1) X-linked sideroblastic anemia (XLSA) - heme biosynthesis disease, not strictly a porphyria
2) X-linked dominant erythropoietic protoporphyria - due to excess ALAS2

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19
Q

What is the second step of heme synthesis?

A

Delta-aminolevulinic acid (ALA) –> (delta-aminolevulinic acid dehydratase) Porphobilinogen

  • Inhibited by Pb
  • Subunit formation via dimerization with double condensation - water moved b/w the two to form a pyrrole ring
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20
Q

What is the third step of heme synthesis?

A

Porphobilinogen –> (Porphobilinogen deaminase/HMB synthase) Hydroxymethybilane (HMB) linear tetrapyrrole intermediate + NH3
*Links four of the porphobilinogen with elimination of an ammonia to form a linear tetrapyrrole intermediate

21
Q

What is the “dead-end” pathway in heme synthesis?

A

1) The linear tetrapyrrole intermediate from step 3 - HMB - undergoes spontaneous cyclization to form Uroporphyringoen 1 (side chains of pyrrole four are symmetric with the side chains of pyrrole two)
* Color/photosensitivity - Uroporphyrin I
2) Uroporphyrinogen 1 –> (uroporphyrinogen I decarboxylase) Coproporphyringoen 1
* Color/photosensitivity - Coproporphyrin I
* This then reaches a dead end and the process can no longer continue

22
Q

What is the fourth step of heme synthesis?

A

Linear intermediate HMB undergoes cyclization –> (Uroporphyrinogen III synthase) Uroporphyrinogen III

  • Cyclization flips the side chains of the fourth pyrrole ring to make them asymmetric with the second pyrrole ring
  • This is termed the productive pathway
23
Q

What is the fifth step of heme synthesis?

A

Uroporphyrinogen III –> (Uroporphyrinogen III decarboxylase) Coproporphyrinogen III
*All the “A” side chains become methyl groups

24
Q

What is the sixth step of heme synthesis?

A

Coproporphyrinogen III –> (Coproporphyrinogen III oxidase) Protoporphyrinogen IX
*Two of the propionyls on pyrrole rings I and II become vinyls as they enter into the mitochondria

25
Q

What is the seventh step of heme synthesis?

A

Protoporphyrinogen IX –> (Protoporphyrinogen IX oxidase) Protoporphyrin IX
*Oxidation of the methylene bridges generates double bonds, giving resonance and color

26
Q

What is the eighth and final step of heme synthesis?

A

Protoporphyrin IX + Fe2+ –> (Ferrochelatase) Heme

  • Reaction can occur spontaneously w/o the enzyme, but at a much slower rate
  • Insertion of ferrous iron completes synthesis
  • Inhibited by Pb and will result in a central Zn2+ instead of Fe2+ - Zn protoporphyrin IX
27
Q

Vitamin B6 deficiency causes?

A

*Results in reduced ALAS activity in step 1, leading to microcytic hypochromic anemia

28
Q

Lead toxicity causes?

A
  • Anemia due to inhibition at steps 2 (ALA dehydratase) and 8 (ferrochelatase)
  • Accumulation of delta-aminolevulinic acid (ALA) and Zn protoporphyrin IX
29
Q

Porphyrias cause?

A
  • Usually due to partial deficiency of a heme biosynthetic enzyme and any of the 8 enzymes can be affected
  • Porphyrins accumulate and their precursors and side products causing symptoms and signs (not invariant) such as:
    • Purple or red urine (teeth)
    • Photosensitivity, skin lesions, increased hair growth
    • Acute attacks of pain, neuropathy, vomiting, confusion
30
Q

Name two famous people who suffered from Acute Intermittent Porphyria

A

1) Vincent van Goh

2) King George III

31
Q

What is the etiology of porphyrias?

A
  • Often genetic - usually autosomal dominant
  • Rarely autosomal recessive [2,4] or X-linked dominant and X-linked recessive ALAS2 defects [1]
  • Low penetrance, often latent or silent
  • Predisposing factors include stress, hormones, drugs, sunlight, diet, infection
32
Q

Three most commonest types of porphyria

A

1) Porphyria cutanea tarda
2) Acute Intermittent Porphyria
3) Erythropoietic Protoporphyria

33
Q

Porphyria Cutanea Tarda

A
  • Defects of uroporphyrinogen decarboxylase, often environmental
  • Most common type and usually caused by liver damage (alcohol, hepatitis C virus)
  • Skin symptoms (due to reactive oxygen species generated by photoactivated porphyrinogens)
  • Uroporphyrinogens (I and III) accumulate in the liver, plasma, urine and stool
  • Slow, often doesn’t show up until middle age (20s, 30s or 40s)
34
Q

Acute Intermittent Porphyria

A
  • Caused by a mutation in porphobilinogen deaminase, auto dominant
  • Often triggered by alcohol, some drugs
  • Characterized by neurological symptoms which can be severe but lacks skin disease b/c porphyrinogens are not created
  • ALA and porphobilinogen accumulate in the plasma, urine (darkens on standing)
35
Q

Erythropoietic Protoporphyria

A
  • Mutations in ferrochelatase, dominant/recessive
  • Most common erythropoietic type and mainly has skin symptoms initially (acute photosensitivity)
  • Protoporphyrin IX accumulates in bone marrow, RBCs, plasma, bile and feces (not urine b/c it is insoluble)
36
Q

Variegate Porphyria

A
  • Mutations in protoporphyrinogen oxidase
  • Frequent in South Africa (Dutch origin, 1 in 300), some in Chile and less in Finland - due to founder effect
  • Presents with neurological and skin symptoms
  • Protoporphyrinogen IX accumulates
37
Q

Name the steps of heme degradation

A

In reticuloendothelial system (aka RES) consisting of fixed mononuclear phagocytes within the spleen, liver, marrow
1) Oxidative cleavage of heme at the carbon joining the first and second pyrrole ring groups + NADPH + O2 via heme oxygenase - linearizes heme –> biliverdin (green color) + Fe3+ + CO (only reaction which generates CO in the body)
2. Biliverdin + NADPH –> (Biliverdin reductase) Bilirubin (insoluble, free) + NADP+
3. Bilirubin is solubilized by binding albumin in the blood (which can bind 2 at a time) - “bound bilirubin”
4. Transported in the blood and then removed from the blood by the liver, where it is conjugated to two molecules of glucuronic acid –> bilirubin diglucuronide and monoglucuronide - to make it soluble (conjugated bilirubin)
5. Once it becomes conjugated bilirubin, it travels to the bile duct and into the small intestine
6. Once it becomes conjugated bilirubin, it travels through the bile duct and into the small intestine
7. Intestine: Bilirubin –> urobilinogen –> stercobilinogen, stercobilin –> feces OR
Kidney: Urobilinogen –> kidneys –> urobilin –> urine OR
Urobilinogen travels through the portal system and goes back to the liver and then traveling back to the intestine

38
Q

What is the first step of heme degradation?

A

Oxidative cleavage of heme at the carbon joining the first and second pyrrole ring groups + NADPH + O2 via heme oxygenase - linearizes heme –> biliverdin (green color) + Fe3+ + CO (only reaction which generates CO in the body)

39
Q

What is the second step of heme degradation?

A

Biliverdin + NADPH –> (Biliverdin reductase) Bilirubin (insoluble) + NADP+

40
Q

What are the two types of heme oxygenase (HMOX)?

A
  • HMOX2 is constitutively expressed - aka “housekeeping” gene
  • HMOX1 is rate limiting - induced by heme, heavy metals and stress (hypoxia)
41
Q

What is the final step of heme degradation in the intestine?

A

Bilirubin –> urobilinogen –> stercobilinogen, stercobilin –> feces OR urobilinogen travels through the portal system and goes back to the liver and then traveling back to the intestine

42
Q

What is the final step of heme degradation in the kidneys?

A

Urobilinogen –> kidneys –> urobilin –> urine

43
Q

Jaundice

A
  • Often a sign of problems with the liver, gallbladder or pancreas or infection (i.e. malaria)
  • Results from hyperbilirubinemia due to:
    • Prehepatic - excessive RBC lysis
    • Hepatic - impaired or inadequate liver function
    • Posthepatic - bile duct obstruction
  • Bilirubin in plasma impartas a yellowish tint to conjunctive and skin
  • Subsequent products increase or decrease or unaltered, depending on cause and severity
  • Dx requires comprehensive tests (i.e. liver function, splenomegaly - accounts for prehepatic) as well as tests for heme degradation products
44
Q

Prehepatic Jaundice

A
  • Hemolytic jaundice - bilirubin (and further degradation products) accumulate i.e. bilirubin:albumin, bilirubin diglucuronide, urobilinogen, urobilin, stercobilin
  • Darker urine and darker feces
45
Q

Hepatic jaundice

A

1) Impaired bilirubin conjugation - hyperbilirubinemia unconjugated
* neonatal jaundice (developmental), Crigler-Najar and Gilbert syndromes (last two are genetic deficiencies of bilirubin UDP-glucuronyl transferase)
2) Impaired or deficient transport of conjugated bilirubin - doesn’t get transported through the cells to the bile duct, hyperbilirubinemia conjugate
* Dubin-Johnson and Rotor Syndromes - genetic deficiencies of intracellular transport genes
3) Both, wide scale liver damage - due to viral hepatitis, liver cirrhosis

  • Conjugated bilirubin (but not unconjugated) can appear in urine - urine dark, feces often light
  • If the transport is deficient - darker urine and lighter feces
  • If conjugation deficient - lighter urine and feces
46
Q

Posthepatic Jaundice

A
  • Obstructive jaundice - feces pale, urine dark
  • Caused by gallstones, pancreatic cancer, parasitic infection, primary biliary cirrhosis
  • Bilirubin diglucuronide enters circulation, bilirubin, stercobilinogen, urobilin all decrease, while Bilirubin diglucuronide and bilirubin:albumin increases
47
Q

What is the van den Bergh reaction used for?

A

Bilirubin (must be in solution - not free or bound to albumin - to react, conjugated is soluble in water and unconjugated can be solubilized with alcohol) + diazonium salts (colorless) –> azo dye (red-purple color)

  • Clinical assay used to assess bilirubin in serum or plasma
  • Bilirubin is reacted with diazonium salts, once with and once w/o alcohol

1) Direct (serum) - reacted w/o alcohol to measure the conjugated (soluble) amount –> yields color
2) Total (serum + methanol) - reacted with alcohol to measure the conjugated and unconjugated amount which are both now soluble and yield a color
3) Use subtraction to determine the indirect (i.e. unconjugated) amount = total - direct

48
Q

Gilbert Syndrome

A
  • Impacted Alexandr Dolgopolv, Arthur Kornberg (Nobel prize winning biochemist in 1959 for identifying the DNA polymerase enzyme)
  • Episodic mild hepatic jaundice
  • Tiredness
  • Weakness
  • Elevated unconjugated bilirubin

Medical Biochemistry and Genetics (4 decks)

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