A potential biochemical explanation for the genesis of porphyria cutanea tarda: Studies on the inherent biochemical defect in highly purified human erythrocyte uroporphyrinogen decarboxylase and its amplification by iron

Familial porphyria cutanea tarda (PCT) is a photocutaneous disease in which subnormal activity of uroporphyrinogen decarboxylase is observed both in the liver and red cells. Hepatic iron plays a key role in the genesis of overt biochemical and clinical PCT. In this report, we have studied the properties of 10000-fold purified erythrocyte uroporphyrinogen decarboxylase preparations from two familial PCT patients and a non-porphyric control subject. The apparent Michaelis constants ( K m), determined by using uroporphyrinogen III substrate, were approx. 3.2-times higher for the enzyme from the diseased subjects ( K m = ~1.0 μM) as compared to the normal ( K m = 0.3 μM). Though both abnormal and normal enzymes were inhibited progressively with increasing concentrations of iron, the enzymes from diseased subjects exhibited greater susceptibility e.g. 0.1 mM Fe 2+ inhibited the former about 50% and the latter about 20%. These observations suggest that (i) the inherent biochemical defect in PCT is the reduced enzyme-substrate affinity and (ii) the intrinsic abnormal conformation renders the PCT enzyme particularly susceptible to inhibition by iron.