Which is the inhibition of which of the following enzymes of heme biosynthesis?

An 18-month-old boy was referred to the pediatrics clinic because of persistent anemia and associated failure to thrive. Laboratory analysis confirmed a microcytic anemia and revealed blood lead-levels of 50 mg/dL(2 times normal levels) and high levels of coproporphyrinogen III in the urine. The child was put on chelation therapy and recovered uneventfully. The cause of the child’s difficulty was most likely due to the effects of lead which is the inhibition of which of the following enzymes of heme biosynthesis?

(A) delta-aminolevulinic acid (ALA) dehydratase
(B) ferrochelatase
© porphobilinogen (PBG) deaminase
(D) proporphyrinogen III cosynthase
(E) uroporphyrinogen decarboxylase

Explanation:

(B) Three enzymes of the heme biosynthesis pathway are targets of the toxic effects of lead. These include ferrochelatase, ALAdehydratase (choice A), and ALA synthase with ferrochelatase sensitivity to lead being greatest and thus the most significant in lead poisoning. The ability to distinguish between inhibition of ferrochelatase and ALAdehydratase is the fact that high levels of coproporphyrinogen III were found in the urine. Since this heme biosynthetic intermediate is downstream of the ALA dehydratase-catalyzed reaction, inhibition of this enzyme would not result in the observed
urine analysis result. Lead does not inhibit the activities of PBG deaminase (choice C), proporphyrinogen III cosynthase (choice D) nor uroporphyrinogen decarboxylase (choice E).