Repression of ALA-Synthetase by Heme

In Rhodopseudomonas spheroides [Lascelles and Hatch, 106] there is some evidence (Section Vlll) that heme represses ALA-synthetase formation. In mutants that could not make heme, more ALA-synthetase was found to accumulate than in wild type. On low iron, less heme was formed and more coproporphyrin accumulated, a result suggesting that, because heme was lacking, more ALA-synthetase was formed the latter action could be explained on the basis of either inhibition or repression of the enzyme by heme. 

A biphasic curve of ALA-synthetase activity of liver mitochondria of rats, induced by AlA and possible involving repression by heme, was first observed by Narisawa and Kikuchi [107]. The enzyme activity increased slightly during the first 12 hours, then remained unchanged for several hours, and then continued to increase during the next 24 hours to tenfold the control value. No biphasic curve was observed with DDC by Wada et al. [86]. Waxman et al. [108] reported that, after the establishment of induced ALA-synthetase in the rat for 3 days, the administration of 2 mg of hemin initiated a series of cyclic oscillations of ALA-synthetase activity with a period of 8 to 12 hours the oscillations continued for 3 days. To explain these oscillations they postulated a repression by heme of the synthesis of ALA-synthetase and thence an overshoot of abnormally increased synthesis. 

The inducing effect of chemicals that bring about a three- to four-fold increase in liver ALA-synthetase in 6 hours was found by Marver [109] to be nullified if simultaneously with the inducing chemical the large dose of 12 mg of hemin chloride (per 100 gm wt) was injected into the rat. 

Experiments on the addition of hemin to the culture medium of chick embyro liver cells [25] showed that relatively low concentrations of hemin (2 x 10 M) decreased porphyrin synthesis by half. Iron deuteroporphyrin and manganese protoporphyrin were less inhibitory. 

Theoretically, heme might repress at the transcriptional or translational level. Evidence that heme acts at the translational level has been obtained by using chick embyro liver cells in culture (Section VI). 

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