ALA-dehydrase

Lead inactivates many enzjnnes including ALA dehydrase and ferrochelatase (hetne synthase), and can produce a microcytic sideroblastic anemia with ringed sideroblasts in the bone marrow. Other symptoms include ... 

Answer C. Lead inhibits both ferrochelatase (increasing the zinc protoporphyrin) and ALA dehydrase (increasing 5-ALA). 

Lead inhibits ALA dehydrase, which biocks the condensation of ALA moiecuies into porphobiiinogen. 

Ferrochelatase and ALA dehydrase are particularly sensitive to inhibition by lead... 

Heavy metals stimulate or inhibit a wide variety of enzyme systems (16, 71, 72), sometimes for protracted periods (71, 73). These effects may be so sensitive as to precede overt toxicity as in the case of lead-induced inhibition of 8 ALA dehydrase activity with consequential interference of heme and porphyrin synthesis (15, 16). Urinary excretion of 8 ALA is also a sensitive indicator of lead absorption (74). Another erythrocytic enzyme, glucose-6-phosphatase, when present in abnormally low amounts, may increase susceptibility to lead intoxication (75), and for this reason, screens to detect such affected persons in lead-related injuries have been suggested (76). Biochemical bases for trace element toxicity have been described for the heavy metals (16), selenium (77), fluoride (78), and cobalt (79). Heavy metal metabolic injury, in addition to producing primary toxicity, can adversely alter drug detoxification mechanisms (80, 81), with possible secondary consequences for that portion of the population on medication. 

Aminolevulinic acid dehydrase (ALA dehydrase) is the second enzyme of the heme biosynthetic pathway. It catalyzes the condensations of two molecules of ALA to form porphyrobilinogen (PBG). 

Succimer produces a lead diuresis with a subsequent lowering of blood lead levels and attenuation of the untoward biochemical effects of lead, manifested by normalization of 5-ALA dehydrase activity. The succimer-lead chelate also is eliminated in bile the fraction eliminated undergoes enterohepatic circulation. 

Subsequently it was shown using [ N]glycine that all 4 nitrogen atoms in protoporphyrin were derived from that amino acid [372]. It is now known that one molecule of glycine and one molecule of succinyl-CoA condense to form one molecule of a-aminolaevulinic acid (ALA). Two molecules of ALA are then linked by the action of cytoplasmic ALA dehydrase to form porphobilinogen (PBG). Four molecules of PBG form a tetrapyrrole, uroporphyrinogen, and subsequently by decarboxylation and oxidation of the side chains, protoporphyrin IX is formed which combines with iron to form haem. Use has been made of both and precursors to elucidate the intermediate steps involved in haem synthesis [373—378]. Much of the early work covering the biosynthesis of porphyrin has been reviewed in detail [379]. 

ALA, ALA-D = aminolevulinic acid dehydrase NCV = nerve conduction velocity... 

Formation of porphobilinogen The dehydration of two molecules of ALA to form porphobilinogen by 8-aminolevulinic acid dehydrase is extremely sensitive to inhibition by heavy metal ions (see Figure 21.3, and p. 279). This inhibition is, in part, responsible for the elevation in ALA and the anemia seen in lead poisoning. 

Levels of delta-aminolevulinic acid (ALA) in the urine are also used as a measure of lead exposure. Increasing concentrations of ALA are believed to result from the inhibition of the enzyme delta-aminolevulinic acid dehydrase (ALA-D). Although the test is relatively easy to perform, inexpensive, and rapid, the disadvantages include variability in results, the necessity to collect a complete 24 hour urine sample which has a specific gravity greater than 1.010, and also the fact that ALA decomposes in the presence of light. 

FIGURE 17-5. Effects of lead on heme synthesis. Enzymes inhibited by lead are in italics. ALA aminolevulinic acid -ALAD = 5 amlnolevulinic acid dehydrase sucdnyl CoA = succinyl coenzyme A. 

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