Porphyria - enzyme defects and accumulated metabolites by type
Core concept
- Haem synthesis - 8 steps, mitochondrion -> cytosol -> mitochondrion
- ALA synthase (rate-limiting, mitochondrial) - repressed by haem via negative feedback
- -> ALA -> ALA dehydratase -> PBG -> PBG deaminase -> HMB -> ... -> protoporphyrin IX -> ferrochelatase (+ Fe2+) -> haem
- The block determines the phenotype
- Early block (before porphyrinogens) -> accumulate ALA and PBG -> neurovisceral attacks, no photosensitivity
- Later block -> accumulate porphyrins (conjugated tetrapyrroles) -> photosensitivity (absorb ~400 nm Soret band -> ROS)
- Both -> acute attacks and skin disease (VP, HCP)
- Why attacks happen: any stimulus that induces hepatic CYP450 consumes haem -> dec feedback -> inc ALA synthase -> substrate floods a partially blocked pathway
3 more sections, plus exam facts
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