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Topics in Medical Biosciences > Heme Metabolism > Flashcards

Heme Metabolism Flashcards

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USMLE® Step 1 flashcards
1
Q

Why do we have to build our own heme in the body?

A

Cannot be renewed, even if consumed

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2
Q

What are porphyrins?

A

Porphyrins are tetrapyrrole macrocyles with substituent side chains.
- bridged
- 4 Coloured pyrrole rings
- Each pyrrole ring is connected to each other with links
○ Contain Nitrogen
○ Side chains - pointing outwards
- Typically complexed with a mental

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3
Q

Name 5 diverse functions of metalloporphyrins in nature.

A 
Chlorophyll
Co-enzyme F430
Vitamin B18
Haemoglobin/ Myoglobin
Cytochromes
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4
Q

What metal is in chlorophyll?

A

Mg

  • Alternating bonds
  • So they can absorb light
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5
Q

What metal is in co-enzyme F430?

A

Ni2+

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6
Q

Where is co-enzyme F430 found?

A

Bacteria

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7
Q

What metal is in Haemoglobin/ Myoglobin?

A

Fe2+

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8
Q

What metal is in cytochromes?

A

Iron

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9
Q

What is the Heme structure like?

A
  • protoporphyrin IX
  • stable
  • planar
  • conjugated
  • absorbs light
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10
Q

What are the Heme synthesis steps?

A
  1. In mitochondria:
    - Glycine provides the N’s and is the starting point
    - Glycine + Succinyl CoA —— (Vit. B6) –> δ-aminolaevulinic acid
    - Product is released out of mitochondria
  2. In cytosol:
    δ-aminolaevulinic acid ——> porphobilinogen (1 porphyrin ring)
  3. 4 X porphobilinogen ———> Uroporphyrinogen (pre-crusor)
  4. Uroporphyrinogen ——-> Coproporphyrinogen
    - Product released back into mitochondria
  5. In mitochondria:
    Coproporphyrinogen ——OXIDATION—-> Protoporphyrin
  6. Protoporphyrin —– INSERTION OF ION—–> Haem
    - Fe from diet
    ○ Carried in our blood attached to a protein
    ○ Fe3+-apo transferin (free iron in our blood will create radicals)
    - Recepto-mediated endocytosis of the iron-protein complex brings in Fe
    -Released Fe is stored as Ferritin in the bone marrow
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11
Q

How many molecules of glycine and succinyl-coA is needed for 1 molecule of heme?

A

8

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12
Q

What enzyme catalyses Glycine + Succinyl CoA into δ-aminolaevulinic acid

A

δ-aminolaevulinate synthase (ALAS)

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13
Q

What inhibits δ-aminolaevulinate synthase?

A

Lead

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14
Q

Where is ALAS1 found?

A
  • housekeeping enzyme of most cells

- liver cells

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15
Q

Where is ALAS2 found?

A
  • erythroid-specific cells

- highly regulated via allosteric feedback

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16
Q

What enzyme catalyses step 2 of heme synthesis?

A

δ-aminolaevulinic acid Dehydratase

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17
Q

What enzyme catalyses step 3 of heme synthesis?

A

Porphobilinogen deaminase

18
Q

What enzyme catalyses step 4 of heme synthesis?

A

Uropophyrinogen III cosynthase

19
Q

What enzyme catalyses step 5 of heme synthesis?

A

Uropophyrinogen decarboxylase

20
Q

What enzyme catalyses step 6 of heme synthesis?

A

Coproporphyrinogen oxidase

21
Q

What enzyme catalyses step 7 of heme synthesis?

A

Protoporphyrinogen oxidase

22
Q

What enzyme catalyses the last step of heme synthesis?

A

Ferrochelatase

23
Q

Describe a genetic disorder that is due to a deficiency of porphobilinogen deaminase (PBGD).

A

Acute Intermittent Porphyria.
- porphyrin precursors, porphobilinogen (PBG) and ALA accumulates in the body
- condition can be activated by puberty, drugs, hormones or diet
DIAGNOSIS: a urine test will show the PBG levels to be 5 times the normal value
TREATMENT: discontinue usage of drugs (if triggering) and a high carbohydrate infusion

24
Q

Describe a genetic disorder that results in a build up of porphyrins.

A

Porphyria Cutanea Tarda (PCT).
- Uropophyrinogen decarboxylase enzyme disorder resulting in the build up of porphyrins in the liver
- substrates for the enzyme are oxidised and transported to the skin, causing photosensitivity
- risk factors incl excessive alcohol consumption, hormone replacement therapy (can be inherited)
DIAGNOSIS: Blistering skin lesions and presence of risk factors
TREATMENT: Reduce iron levels by removing blood

25
Q

How can damaging by-products be made from heme synthesis?

A

Lots of potential for side reactions. Where the Uropophyrinogen III cosynthase goes on way, there is a non-enzymatic reaction that occurs that does not form heme and creates damaging by-products that accumulate in tissue

26
Q

What are porphyrinogens?

A

reduced precursors of protoporphyrin IX.

27
Q

How is heme synthesis regulated? specifically for ALAS1

A

Heme controls ALAS1 activity by 3 mechanisms:
- negatively controlling transcription, mRNA stabilisation, ALAS1 processing
- feedback inhibition of ALAS1
- inhibition of translocation of ALAS1 from cytosol
ALAS1 can also be greatly induced by the administration of many drugs - creating the demand for Heme
- deplete the heme pool and de-repress ALAS1

28
Q

What cytochrome is heme required for?

A

CytP450

29
Q

How is heme synthesis regulated? specifically for ALAS2

A

expression of ALAS2 is regulated primarily by Fe availability

30
Q

What are Porphyrias?

A

A group of rare inherited disorders caused by deficiencies of enzymes of the heme biosynthetic pathway. Can lead to reduced level of heme synthesis, control of heme production, accumulation of toxic products, increase risk of liver cancer

31
Q

What are the 5 P’s for the symptoms of patients suffering from Acute Intermittent Porphyria (AIP)?

A 
Pain in abdomen
Polyneuropathy
Psychological disturbances
Pink/ port urine
Precipitated by drugs
32
Q

How do you treat / manage an acute porphyria attack?

A

Identify and eliminate triggers
Go against standard practice of carbohydrate restriction
Give IV heme

33
Q

Where does Heme catabolism occur?

A

Liver, Spleen and Bone Marrow

34
Q

What are the 2 steps of Heme catabolism?

A
  1. Cleavage of the heme ring by heme oxygenase (needs heme, 3 Oxygen molecules and NADPH) creating Biliverdin, CO, Iron2+ and NADP+
  2. Biliverdin gets reduced by Biliverdin reductase producing unconjugated Bilirubin - with the help of NADPH as a reducing agent
35
Q

How can you turn unconjugated Biligrubin into its conjugated form?

A

Addition of sugars via UDP-glucoronate. The BR is bound to serum albumin which is transferred into the liver where it is conjugated.

36
Q

Which is the indirect BR (bilirubin) and which is the direct BR?

A 
Indirect = unconjugated 
Direct = conjugated BR
37
Q

Why is hyperbilirubinaemia bad?

A

BR is highly neurotoxic

  • lipid soluble so can cross membranes
  • both unconj and conj hyperbilirubinaemia can cause jaundice (especially for babies as they have higher quantities of BR anyway)
38
Q

What is the definition of Jaundice?

A

Yellow discolouration of skin and sclera as a result of hyperbilirubinaemia

39
Q

State an example of a case that unconjugated hyperbilirubinaemia has occured by overproduction of bilirubin.

A

Jaundice in babies

Can be resolved using phototherapy as it triggers spontaneous breakdown of the accumulated unconjugated BR

40
Q

State an example of a case that conjugated hyperbilirubinaemia.

A

Caused by an obstruction due to liver/ biliary tract disease - alcohol abuse or hepatitis. Fails to conjugate or secrete the conjugated BR into the bile ducts.

Topics in Medical Biosciences (12 decks)

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