8-Aminolaevulinic acid synthase

Lead Lead poisoning (= saturnism) results in mild, rapidly regressive toxic hepatitis in about 30% of cases. Occasionally, eosinophilic, acid-resistant inclusions are found in the nuclei of the liver cells (so-called lead protein complexes). Steatosis and liver-cell necrosis have also been witnessed. Although there is a correlation between exposure to lead and severity of damage, individual sensitivity to lead can nevertheless vary. In addition, lead intoxication causes an inhibition of erythrocyte 5-aminolaevulinic acid dehydratase and an induction of 5-aminolaevulinic acid synthase. This brings about the manifestation of acute intermittent porphyria. (8)... 

Fraser DJ, Podvinec M, Kaufmann MR, Meyer UA. Drugs mediate the transcriptional activation of 5-aminolaevulinic acid synthase (ALASl) gene via the chicken xenobiotic-sensing nuclear receptor (CXR). J Biol Chem 2002 277 34717-26. 

Wakao N, Yokoi N, Isoyama N, Hiraishi A, Shimada K, Kobayashi M, Kise H, Iwaki M, Itoh S, Takaichi S, Sakurai Y (1996) Discovery of natural photosynthesis using Zn-containing bacte-riochlorophyll in aerobic bacterium Acidiphilum rubrum. Plant Cell Physiol 37 889-893 Warren MJ, Bolt E, Woodcock SC (1994) 5-Aminolaevulinic acid synthase and uroporphyrinogen methylase two control enzymes of tetrapyrrole biosynthesis and modification. In Biosynthesis of the tetrapyrrole pigments (Ciba foundation symposium 180). Wiley, Chichester, pp 26—40... 

ALA synthase is a pyridoxal phosphate-dependent enzyme and promotes Schiff-base formation between its coenzyme and glycine (67 in Fig. 37). Nucleophilicity at C-2 of the glycine could be generated either by decarboxylation or by abstraction of a proton. In the first case 5-aminolaevulinic acid would retain both methylene protons of glycine, in the second, one of the protons would be lost to the medium (Fig. 37). Acylation of the pyridoxal-bound intermediate (68 or 69) by succinyl-CoA would constitute the next step and this could be followed either by direct hydrolysis of the Schiff-base or by decarboxylation with subsequent hydrolysis depending on which course was chosen in the first stage of the reaction. 

In healthy people, forming haemoglobin for their erythrocytes and haem-dependent enzymes, the rate of haem synthesis is controlled by negative feedback according to the amount of haem present. When more haem is needed there is increased production of the rate-controlling enzyme delta-aminolaevulinic acid (ALA) synthase which provides the basis of the formation of porphyrin precursors of haem. But in people with porphyria one or other of the enzymes that convert the various porphyrins to haem is deficient and so porphyrins accumulate. A vicious cycle occurs less haem —> more ALA synthase —> more porphyrin precursors, the metabolism of which is blocked, and a clinical attack occurs. 

ALA synthase can be suppressed by glucose. Due to the short half-life of ALA synthase of 70-80 minutes, inhibition or induction of this enzyme very quickly affects haem synthesis. Haem deficiency due to an enzyme defect causes an increase in 5-aminolaevulinic acid. Free haem is either integrated into various apoproteins or it intervenes as a haem repressor with the nuclear gene chain, which leads to the formation of specific mRNA for ALA synthase. Synthesis and consumption of haem are synchronized precisely. The organism produces some 300 mg haem per day, with only 1% being excreted unused in the urine or faeces. (271, 273, 300, 309) (s. p. 34) (s. tab. 3.3)... 

Lead (Pb) inhibits poiphobilinogen synthase and Fe" incorporation into haem, resulting in increased levels of 5-aminolaevulinic acid and coproporphyrin in urine and protoporphyrin in erythrocytes. 

The first product formed by condensation of glycine and succinyl CoA is 5-aminolaevulinic acid or ALA. This reaction is catalysed by the enzyme ALA synthase and requires the cofactor, p)rridoxyl phosphate. ALA synthesis occurs entirely within the matrix of the mitochondrion and is very tightly regulated by control of the enzyme that makes it, control of the transport of the enzyme from the cytosol into the mitochondrion, and finally by inhibition of ALA synthase by the final product, heme. 

---