In the mitochondria of red blood cell precursors, glycine + succinyl-CoA are combined by synthase (ALAS) into δ-aminolevulinic acid (ALA) — the 5-carbon starting point of heme synthesis.This step requires vitamin B6 (PLP) as a cofactor, so B6 deficiency stalls step 1 and presents as "microcytic hypochromic anemia," which looks like iron deficiency but is actually a synthesis bottleneck.
2 · Cytosol: porphyrin ring
leaves the mitochondria for the cytosol, where reactions assemble it into a porphyrin ring; the zinc enzyme at step 2 is the first target of lead poisoning.2 × → porphobilinogen (PBG) — the step-2 enzyme ALA dehydratase (ALA-D) is a zinc-containing enzyme and the first target of lead poisoning. Then 4 × PBG → linear tetrapyrrole → ring closure → uroporphyrinogen III → coproporphyrinogen III — a total of 6 cytosolic steps assemble 8 molecules into a porphyrin ring with 4 nitrogen atoms.
3 · Insert Fe²⁺ → heme
Porphyrin precursors return to the mitochondria, are oxidized to protoporphyrin IX, an empty ring, and finally ferrochelatase inserts Fe²⁺ into its center, completing heme.The bone marrow's 2 million red cells per second means the body produces ~20 mg of new heme per day — of which ~95% of the iron comes from recycled old red cells (spleen + liver + macrophages), and only 1-2 mg net from dietary absorption.
4 · Lead poisoning's chemical fingerprint
Lead displaces the metal in two key enzymes, so piles up and red cells put Zn²⁺ in place of Fe²⁺, raising red-cell zinc protoporphyrin (ZPP).Lead displaces the metal cofactors of two key enzymes: the first target is -D (zinc site) → ALA accumulates → blood/urine ALA ↑; the second target is ferrochelatase → Fe²⁺ can't be inserted → red cells substitute Zn²⁺ → red-cell zinc protoporphyrin (ZPP) ↑. ZPP reflects average exposure over the past few months and is run alongside blood lead in occupational medical surveillance; the decisive test is the blood lead level — ZPP is insensitive to recent or acute exposure.
After the US began phasing lead out of gasoline (1973; the full ban on road-vehicle leaded fuel came only in 1996) and banned leaded paint (1978), the average blood lead in children fell from 15 µg/dL to < 1 µg/dL, and average IQ rose by about 2-5 points — the cognitive damage from chronic low-dose childhood lead exposure is permanent and irreversible.