ferrochelatase

Ferrochelatase (heme synthase) catalyzes the final step of heme synthesis, combining protoporphyrin IX with ferrous iron (Fe2+) to produce heme within the mitochondrial matrix/inner membrane. This step occurs after the pathway shifts back into the mitochondria following cytosolic steps (ALA synthase/ALA dehydratase in mitochondria, then cytosolic steps, then final mitochondrial steps).

Clinical relevance: 1. Erythropoietic protoporphyria (EPP): Autosomal dominant (with low penetrance) partial deficiency of ferrochelatase leads to accumulation of protoporphyrin IX in erythrocytes, skin, and liver. Patients present with painful photosensitivity (non-blistering, burning pain upon sun exposure) due to protoporphyrin-mediated phototoxic reactions, distinguishing it from other porphyrias with blistering lesions. Can rarely cause liver damage from protoporphyrin accumulation.

2. Lead poisoning: Lead inhibits both ferrochelatase and ALA dehydratase, two key enzymes in heme synthesis. This leads to accumulation of protoporphyrin (measured clinically as elevated free erythrocyte protoporphyrin/zinc protoporphyrin) and ALA, causing a sideroblastic, microcytic anemia with basophilic stippling of erythrocytes. Lead poisoning classically presents with abdominal pain, neurologic symptoms (encephalopathy, peripheral neuropathy - wrist/foot drop), and in children, developmental delay and behavioral issues. Radiographically, lead lines can be seen on gingivae (Burton's lines) and long bones.

3. Differentiating porphyrias: Understanding the heme synthesis pathway and enzyme deficiencies helps distinguish different porphyrias - acute intermittent porphyria (porphobilinogen deaminase deficiency, neuro-visceral symptoms without photosensitivity) vs. porphyria cutanea tarda (uroporphyrinogen decarboxylase deficiency, blistering photosensitivity) vs. EPP (ferrochelatase deficiency, painful non-blistering photosensitivity).

High-yield board testing points often involve lead poisoning mechanisms, heme synthesis pathway enzyme order/location, and differentiating porphyria types by enzyme deficiency and clinical presentation.