L32: Heme Metabolism Flashcards
1
Q
Two molecules used to start heme synthesis
A
- Glycine and succinyl-CoA
2
Q
Describe how heme is synthesized
A
- In mito: Glycine and succinyl-CoA acted on by ALA synthase = aminolevulenic acid (ALA) - 2 x ALA molecules acted on by PBG synthase (aka ALA dehydratase) and produce porphobilinogen (PBG) out in cytoplasm - 4 x PBG acted on by PBG deaminase with product fed into UPG III synthase to produce uroporphyrinogen III (UPG III) - UPG III acted on by UPG III decarboxylase to produce coporphyrinogen III (CPG III) - CPG III enters mito again and becomes protoporphyrinogen IX, which is acted on by ferrochelatase which adds Fe2+ to structure causing formation of heme B
3
Q
Regulation of heme synthesis
A
- ALA synthase is regulated by end product (low = activated ez, high = deactivated ez)
4
Q
Describe defects in heme synthesis
A
- AIP: acute intermittent porphyria: deficiency in PBG deaminase, causes build up of PBG and ALA. Give urine a dark red color. Life threatening and causes episodes of confusion and sharp abdominal pain - PCT: porphyria cutanea tarda: deficiency in uroporphyrinogen decarboxylase, leads to buildup of porphyrins (detected in urine). Porphyrins able to absorb visible and UV light. As a result, light energy is builtup and discharged into tissue and generates ROS. As a consequence, PCT causes photosensitivity of skin and leads to blistering of sun-exposed areas.
5
Q
What does enzyme deficiency in PBG deaminase cause?
A
- AIP
6
Q
What does enzyme deficiency in uroporphyrinogen decarboxylase cause?
A
- PCT
7
Q
Describe AIP.
A
- AIP: acute intermittent porphyria: deficiency in PBG deaminase, causes build up of PBG and ALA. Give urine a dark red color. Life threatening and causes episodes of confusion and sharp abdominal pain
8
Q
Describe PCT.
A
- PCT: porphyria cutanea tarda: deficiency in uroporphyrinogen decarboxylase, leads to buildup of porphyrins (detected in urine). Porphyrins able to absorb visible and UV light. As a result, light energy is builtup and discharged into tissue and generates ROS. As a consequence, PCT causes photosensitivity of skin and leads to blistering of sun-exposed areas.
9
Q
What enzyme inserts iron into heme molecule? Where in cell?
A
- Ferrochelatase inserts Fe2+ into protoporphyrinogen IX molecule causing formation of heme B
10
Q
Effect of lead on heme synthesis
A
- Lead inhibits porphobilinogen synthase, causing accumulation of ALA - Lead inhibits ferrochelatase, causing accumulation of protoporphyrinogen IX - Causes symptoms similar to the porphyrias
11
Q
Heme synthesis enzymes affected by lead
A
- Porphobilinogen synthase - Ferrochelatase
12
Q
Why do alcohol and certain drugs trigger a porphyria attack?
A
- Alcohol consumption induces synthesis of cytochromes for the production of cytochrome P450 enzymes of MEOS. In doing so, alcohol leads to accumulation of porphyrin precursors in porphyria pts and is likely to trigger an acute attack - Certain drugs, including barbiturates worsen symptoms of heme synthesis
13
Q
Contrast cytochrome and heme
A
- P450 cytochrome synthesis consumes heme and increases heme synthesis
14
Q
Why do some porphyrias cause photosensitivity?
A
- Porphyrins are conjugated systems, which absorb UV and visible light. - The light energy must be discharged upon being absorbed, so it is discharged into the tissues and generates ROS. As a result photosensitivity of skin occurs
15
Q
Describe heme degradation and excretion
A
- Heme is cleaved between A and B rings by heme oxygenase, yielding biliverdin - Biliverdin reductase used NADPH to form bilirubin, which is unconjugated (aka indirect) - Becomes bound to albumin and travels to liver where it is conjugated to two UGT molecules and becomes bilirubic diglucuronide. This is form that is excreted in bile - When in gut, BDG is modified into urobiliongen by gut and then spontaneously to urobilins / stercobilins which is found in feces - Some urobilinogen is absorbed back into blood and spontaneously converted into urobilin, which is urinated out.
