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 10 000-fold purified erythrocyte uroporphyrinogen decarboxylase preparations from two familial PCT patients and a non-porphyric control subject. The apparent Michaelis constants (Km), determined by using uroporphyrinogen III substrate, were approx. 3.2-times higher for the enzyme from the diseased subjects (Km = approximately 1.0 microM) as compared to the normal (Km = 0.3 microM). 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 Fe2+ inhibited the former about 50% and the latter about 20%. These observations suggest that the inherent biochemical defect in PCT is the reduced enzyme-substrate affinity and the intrinsic abnormal conformation renders the PCT enzyme particularly susceptible to inhibition by iron.
D002262:Carboxy-Lyases / Q000097:blood*; D004912:Erythrocytes / Q000201:enzymology*; D006801:Humans; D007501:Iron / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D011164:Porphyrias / Q000201:enzymology / Q000209:etiology*; D012871:Skin Diseases / Q000201:enzymology / Q000209:etiology*; D014575:Uroporphyrinogen Decarboxylase / Q000097:blood*
D007501:Iron; D002262:Carboxy-Lyases; D014575:Uroporphyrinogen Decarboxylase