5-Aminolevulinic acid dehydrase

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). 

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

Haeger-Aronsen B, Abdulla M, Fristedt BI. 1971. Effect of lead on 8-aminolevulinic acid dehydrase activity in red blood cells. Arch Environ Health 23 440-445. 

Hemberg S, Nikkanen J, Mellin G, et al. 1970. delta-Aminolevulinic acid dehydrase as a measure of lead exposure. Arch Environ Health 21 140-145. 

Nieburg PI, Weiner LS, Oski BF, et al. 1974. Red blood cell delta-aminolevulinic acid dehydrase activity. Am J Dis Child 127 348-350. 

Secchi GC, Erba L, Cambiaghi G. 1974. Delta-aminolevulinic acid dehydrase, activity of erythrocytes and liver tissue in man Relationship to lead exposure. Arch Environ Health 28 130-132. 

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. 

Correct answer = B. The activity of 6-aminole-vulinic acid synthase controls the rate of por phyrin synthesis. The enzyme is increased in patients treated with certain drugs, and requires pyridoxal phosphate as a coenzyme. Another enzyme in the pathway ( -aminolevulinic acid dehydrase) is extremely sensitive to the pres ence of heavy metals. 

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. 

Doss, M., Becker, U., Sixel, E., Geisse, S., Solcher, H., Schneider, J., 1982. Persistent proto-porphyrinemia in hereditary porphobilinogen synthase (8-aminolevulinic acid dehydrase) deficiency under low lead exposure a new molecular basis for the pathogenesis of lead intoxication. Klin. Wochenscr. 60, 599-606. 

Inhibition of the enzymes S-aminolevulinic acid dehydrase (5>ALAD), heme synthetase, and ferrochdatase reduces heme syndiesis and causes accumulation of heme precursors (e.g., aminolevulinic acid, coproporphyrins, zinc protoporphyrin) in the blood. 

The answer is 2 [Chapter 16 III B 2b (I) (c)l. Porphyrins that are produced after 6-aminolevulinic acid dehydrase (8-ALAD) is inhibited would be photodynamic if they reached the fluids of the subcutaneous tissue and dermis. Protoporphyrins, the porphyrins resulting from lead toxicosis, are chelated by zinc, which prevents them from exiting the erythrocytes. Thus, photosensitization Is not a clinical feature of the porphyria produced by lead poisoning. 

Beyond pharmaceutical screening activity developed on aminothiazoles derivatives, some studies at the molecular level were performed. Thus 2-aminothiazole was shown to inhibit thiamine biosynthesis (941). Nrridazole (419) affects iron metabohsm (850). The dehydrase for 5-aminolevulinic acid of mouse liver is inhibited by 2-amino-4-(iS-hydroxy-ethyl)thiazole (420) (942) (Scheme 239). l-Phenyl-3-(2-thiazolyl)thiourea (421) is a dopamine fS-hydroxylase inhibitor (943). Compound 422 inhibits the enzyme activity of 3, 5 -nucleotide phosphodiesterase (944). The oxalate salt of 423, an analog of levamisole 424 (945) (Scheme 240),... 

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. 

---