Regulation by heme of synthesis and intracellular translocation of δ-aminolevulinate synthase in the liver

Summary

The primary factor regulating the overall activity of heme biosynthesis in animals is supposed to be the level of ALA synthase in mitochondria. In animals with chemically induced hepatic porphyria, however, a considerable amount of ALA synthase also accumulates in the liver cytosol fraction, although the extent of accumulation is variable according to the species of animals and drugs used. Kinetic studies using a combination of [³H]leucine and an anti-ALA synthase IgG showed that the ALA synthase accumulating in the cytosol is a precursor in transit to mitochondria; the enzyme is transferred into mitochondria at a half-disappearance time of about 20 min. Kinetic studies also revealed that the transfer of ALA synthase from the liver cytosol into mitochondria is strongly inhibited by heme. This inhibition would represent a new mechanism of feedback regulation of metabolism in animal in the sence that the inhibition of intracellular translocation of ALA synthase would bring about reduction of the activity of porphyrin biosynthesis. Taking advantage of the inhibition by heme of the intracellular enzyme translocation, the real half-life of ALA synthase in the rat liver mitochondria was estimated to be about 35 min.

There is evidence that synthesis of ALA synthase is subject to feedback regulation by heme. In mammalian liver, the inhibition by heme appeared to occur mainly at a posttranscriptional step, although the data obtained did not necessarily exclude the possibility that heme also interferes with the transcriptional step.

Comparative study of the effects of administration of hemin on the degree of heme saturation of tryptophan pyrrolase and the extent of inhibition of synthesis and intracellular translocation of ALA synthase revealed a close correlation between the extent of those three events, suggesting that both the synthesis and the intracellular translocation of ALA synthase may be regulated by the variation of ‘regulatory heme’ pool at a physiological range in the liver cell.

ALA synthase in rat liver is synthesized almost exclusively on free polyribosomes and the transfer of the enzyme from the liver cytosol into mitochondria appears to be accompanied with processing of the enzyme protein.