δ-aminolevulinic acid dehydratase

δ-Aminolevulinic acid dehydratase (ALAD), also called porphobilinogen synthase, catalyzes the condensation of two ALA molecules to form porphobilinogen (PBG), the second step of heme biosynthesis occurring in the cytosol. This zinc-dependent enzyme is highly susceptible to inhibition by heavy metals, particularly lead, which displaces zinc and inhibits enzyme activity—this is the biochemical basis of lead poisoning's interference with heme synthesis. Lead poisoning causes accumulation of ALA (since ALA synthase is upregulated due to low heme feedback inhibition, but ALAD is blocked), leading to sideroblastic anemia with basophilic stippling, abdominal pain, neuropathy, and other lead toxicity symptoms.

ALAD deficiency porphyria (Doss porphyria) is an extremely rare autosomal recessive disorder caused by mutations in the ALAD gene, leading to accumulation of ALA and resulting in neurovisceral symptoms similar to acute intermittent porphyria (abdominal pain, neuropathy, psychiatric disturbances) but without photosensitivity, since porphobilinogen and downstream porphyrins are not produced in excess.

Clinically, ALAD is important to remember in the differential diagnosis of microcytic anemia when there's a history of environmental lead exposure (old paint, pottery glaze, occupational exposure). Elevated blood lead levels, elevated free erythrocyte protoporphyrin, and basophilic stippling on peripheral smear support this diagnosis. Understanding the heme synthesis pathway and where various toxins/enzyme deficiencies act is high-yield for boards, including differentiating porphyrias (excess heme precursors) from lead poisoning (enzyme inhibition mimicking porphyria).