Enzyme aspects of acute intermittent porphyria

Summary Patients with acute intermittent porphyria are now known to have a decrease of the third enzyme and, in liver, an increase of the first enzyme of the heme biosynthetic pathway. It is possible that the induction of the first enzyme (ALA synthetase) in the liver of these patients results from the partial block in heme synthesis, since heme is known to be involved in the repression of hepatic ALA synthetase via a closed negative feedback loop. Presumably, an increase of hepatic ALA synthetase allows the delivery of a higher substrate concentration to the enzyme at the level of the block, thus raising the rate of the synthesis of end product toward normal. Using a simplified Michaelis-Menten model of an irreversible pathway in a homogeneous system, quantitative relationships between the degree of block and the magnitude of induction of the first enzyme necessary to return the steady state rate of the pathway to normal have been developed. This is intended as a point of departure for refinements which may ultimately lead to more accurate quantitative relationships.Despite the fact that various forms of experimental porphyria do not produce the specific enzyme decrease of acute intermittent porphyria, they have provided the basis for a number of discoveries which have direct application to this disease.Reprint requests should be sent to this address.