Properties of ALA-Synthetase

The enzyme from mammalian liver mitochondria or the hemolysate residue of bird erythrocyte is inhibited by reagents that react with the pyridoxal moiety such as cysteine, CoASH, and L-penicillamine. These probably react with the aldehyde group of the coenzyme to form a thiazolidine ring HCN can form a cyanohydrin [Gibson et al., 45, 36]. Aminomalonate is also a good inhibitor (Ki = 2x 10 M). 

The preparation of a soluble, somewhat purified ALA-synthetase from purple photosynthetic bacteria has been described. The enzyme is precipated by 30% ammonium sulfate [Kikuchi et al., 37 Shemin et ah, 38]. 

The mechanism of action proposed for ALA-synthetase [Shemin, 39] is the condensation of pyridoxal phosphate with glycine to form a Schiff base on the enzyme, thus forming a stable carbanion with loss of a proton (Fig. 3). This is followed by condensation in which the 

The enzyme from Rhodopseudomoms spheroides has maximal activity [38] at pH 6.9. The K for pyridoxal phosphate is 5 x 10 M, for succinyl-CoA 2.2 x 10 M, and for glycine 3 x 10 M. Inhibitors of this enzyme reveal that SH groups are required for activity. In erythrocytes a-KG is a competitive inhibitor of glycine utilization concentration of a-KG above 1 mM inhibits ALA synthesis. 

Irving and Elliott [59] have observed an inhibitor of ALA-synthetase that resides in an insoluble fraction of noninduced guinea pig mitochondria and that is stable to heat and acid. 

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Now that we have considered the properties of ALA-synthetase, its synthesis and control, and the other factors that affect its activity, let us see how we may explain the symptoms of the hepatic porphyrias. There are two major forms of the disease acute intermittent porphyria (AIP) and porphyria cutanea tarda (PCT) [6,11]. In Table V are listed... 

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