Substrates, Vitamins, and Enzymes Involved in the Synthesis of ALA

Because the synthesis of ALA is the limiting step in heme and chlorophyll biosynthesis, and the ALA is found to be markedly increased under certain conditions, a review of the properties of the enzyme that 

The now classic labeling experiments of Shemin, Rittenberg, and co-workers [39] with glycine, acetate, and succinate led to the recognition that ALA was the first product of the biosynthetic chain of heme. ALA is formed from glycine and succinyl-CoA according to reaction (1). 

The requirement of pyridoxal phosphate for heme synthesis was first shown by a nutritional experiment. In 1950 Wintrobe [47] found that pigs deficient in vitamin Bg formed small, pale, red cells very low in free protoporphyrin, stored excessive iron, and had a h3q)erplastic bone marrow. Lascelles [8] showed that both vitamin Bg and pantothenic acid were required for porphyrin synthesis in Tetrahymena vorax. Similarly, studies by Schulman and Richert [48] showed that heme synthesis in deficient ducklings required vitamin Bg and CoA. 

Equation (1) indicates that a low heme content may be due to a lack of the two vitamins, pyridoxal phosphate and CoA, which are required for the limiting step in porphyrin biosynthesis. The smallness of the red cells in pyridoxal phosphate deficiency is probably due not only to the necessity of this coenzyme for amino acid and heme synthesis, but also to the fact that, without heme, globin is not synthesized. 

Synthesis of succinyl-CoA in mammalian cells such as the red cell and liver cell can be accomplished either from a-KG or from succinate. The formation of succinyl-CoA occurs in the mitochondria as part of the citric acid cycle reactions. The requirement for a citric acid cycle to form ALA or protoporphyrin or heme has been shown by tracer studies with acetate and succinate [39], and by inhibition studies with malonate, Ira j -aconitate, fluoracetate, and arsenite [49]. The requirement for an electron transfer system from the citric acid cycle to O2 has been shown by inhibition studies with anaerobiosis and CO. The requirement for oxidative phosphorylation has been shown by dinitrophenol inhibition of ALA synthesis dinitrophenol may also inhibit ALA-synthetase [3,49]. 

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