Eight-step pathway from succinyl-CoA + glycine to heme. Mitochondrial / cytosolic shuttle: ALAS (rate-limiting, mitochondrial; hepatic ALAS1 + erythroid ALAS2) → δ-aminolevulinic acid (ALA) → cytosolic steps to coproporphyrinogen III → back into mitochondria for protoporphyrinogen → heme (ferrochelatase). Deficiencies of any step produce the porphyrias — acute intermittent porphyria (PBGD), porphyria cutanea tarda (UROD), variegate porphyria (PPOX), erythropoietic protoporphyria (FECH). Lead inhibits ALA dehydratase + ferrochelatase, producing the basophilic stippling + microcytic anemia of plumbism. Iron deficiency limits heme via ferrochelatase substrate exhaustion.
Organ Systems
immune-hematologic
nervous
Pathway Steps
succinyl-coa → aminolevulinic-acid — via ALAS — rate-limiting; ALAS1 (hepatic) vs ALAS2 (erythroid). ALA synthase is the rate-limiting step and requires pyridoxal-5′-phosphate (B6). Hepatic ALAS1 is heme-repressed and drug-inducible (CYP demand → acute porphyria attacks); erythroid ALAS2 is iron/erythropoiesis-regulated and mutated in X-linked sideroblastic anemia.
aminolevulinic-acid → porphobilinogen — via ALA dehydratase — LEAD-INHIBITED. ALA dehydratase (PBGS) condenses two ALA and is zinc-dependent. It is potently lead-inhibited (lead displaces the zinc), so lead poisoning raises ALA and produces a porphyria-like picture.
porphobilinogen → coproporphyrinogen-iii — via multi-step (PBGD → UROS → UROD). Four porphobilinogens assemble into the tetrapyrrole ring: PBG deaminase (HMBS, mutated in acute intermittent porphyria), then UROS and UROD shape and decarboxylate it. UROD deficiency causes porphyria cutanea tarda (photosensitivity).
coproporphyrinogen-iii → protoporphyrin-ix — via CPO → PPOX (mitochondrial re-entry). Coproporphyrinogen oxidase then protoporphyrinogen oxidase complete oxidation as the pathway re-enters the mitochondrion, creating the conjugated ring that will chelate iron. PPOX deficiency causes variegate porphyria.
protoporphyrin-ix → heme — via ferrochelatase — inserts Fe2+; LEAD-INHIBITED. Ferrochelatase inserts ferrous iron (Fe²⁺) into protoporphyrin IX — the final step, also lead-inhibited (lead blocks both ends of the pathway). Its deficiency causes erythropoietic protoporphyria; iron deficiency leaves zinc-protoporphyrin instead.