Aminolaevulinate synthetase

As well as induction of the synthesis of the apoprotein portion of cytochrome P-450, there is also induction of the synthesis of the heme portion. Clearly, it is also necessary to have an increased amount of heme if there is an increase in the amount of the enzyme apoprotein being synthesized. Thus, the rate-limiting step in heme synthesis, the enzyme 5-aminolaevulinate synthetase, is inducible by both phenobarbital and TCDD. This is the result of transcriptional activation of the gene, which codes for the S-aminolaevulinate synthetase. It may be that the decrease in the heme pool, which results from incorporation of heme into the newly synthesized apoprotein, leads to derepression of the gene and hence increased mRNA synthesis. The gene repression could be heme-mediated, or heme may modulate P-450 genes. 

De Matteis, F. and A. Gibbs (1972). Stimulation of liver 5-aminolaevulinate synthetase by drugs and its relevance to drug-induced accumulation of cytochrome P-450. Biochem. J. 126, 1149-1160. 

E. A. Wider de Xifra, J. D. Sandy, R. C. Davies, and A. Neuberger, Control of 5-aminolaevulinate synthetase activity in Rhodopseudomonas spheroides, Philos. Trans. Roy. Soc. London,... 

Reduced synthesis. The synthesis of enzymes may be decreased, resulting in a decrease in the in vivo activity. With cytochrome P-450 there are a number of ways in which this occurs. Thus, administration of the metal cobalt to animals will decrease levels of cytochromes P-450 by inhibiting both the synthesis and increasing the degradation of the enzyme. Thus, cobalt inhibits S-aminolaevulinic acid synthetase, the enzyme involved in heme synthesis. Cobalt will also increase the activity of heme oxygenase, which breaks down the heme portion to biliverdin. The compound 3-amino, 1, 2, 3-triazole decreases cytochromes P-450 levels by inhibiting porphyrin synthesis. 

Aminolaevulinic acid synthetase located in the mitochondrial matrix space (McKay et al, 1969) is the first in a sequence of enzymes involved in heme synthesis and may represent the rate limiting step in its regulation. This enzyme is not synthesized within the mitochondria (Jayaraman et al, 1971 Barnes et al, 1971). 

The classical studies of Shemin [68, 69] identified glycine as one of the precursors of haem, and led to the discovery that glycine and succinyl-coenzyme A are substrates for the enzymic synthesis of 8-aminolaevulinic acid (ALA). The mitochondrial enzyme concerned, ALA-synthetase, is present in both liver and in red cell precursors [70, 71] and requires the presence of pyridoxal phosphate [72]. 

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