Dehydrase

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),... 

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

FIGURE 25.13 Double bonds are introduced into the growing fatty acid chain in E. coli by specific dehydrases. Palmitoleoyl-ACP is synthesized by a sequence of reactions involving four rounds of chain elongation, followed by double bond insertion by /3-hydroxydecanoyl thioester dehydrase and three additional elongation steps. Another elongation cycle produces cA-vaccenic acid. 

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. 

These enzymes catalyse the non-hydrolytic cleavage of bonds in a substrate to remove specific functional groups. Examples include decarboxylases, which remove carboxylic acid groups as carbon dioxide, dehydrases, which remove water, and aldolases. The decarboxylation of pyruvic acid (10.60) to form acetaldehyde (10.61) takes place in the presence of pyruvic decarboxylase (Scheme 10.13), which requires the presence of thiamine pyrophosphate and magnesium ions for activity. 

Scheme 2. Inactivation of (3-hydroxydecanoyl thioester dehydrase by the suicide substrate 3-decynoyl-A/-...

M. Morisaki, K. Bloch, Inhibition of (5 -hyd roxyd ecan-oyl thioester dehydrase by some allenic adds and their thioesters , Bioorg. Chem. 1971,1,188. 

Very few enzymes have been characterized as lactam-forming dehydrases. One exception is carbamoylaspartic dehydrase (EC 3.5.2.3), which catalyzes the cyclization of V-carbamoylaspartic acid to dihydroorotic acid en route to pyrimidines (this enzyme is also known as dihydroorotate amidohydrolase when it catalyzes the reverse reaction). 

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). 

This enzyme [EC 3.5.2.S], also called carbamoylaspartic dehydrase, catalyzes the hydrolysis of (5)-dihydrooro-tate to yield iV-carbamoyl-L-aspartate. 

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

Decarboxylases Dehydrases Oxidoreductases Oxidases Reductases Dehydrogenases Transferases Kinases Transaminases Enzyme cofactors Vitamins... 

Figure 3.8 One complete cycle and the first step in the next cycle of the events during the synthesis of fatty acids. ACP = acyl carrier protein, a complex of six enzymes i.e. acetyl CoA-ACP transacetylase (AT) malonyl CoA-ACP transferase (MT) /3-keto-ACP synthase (KS) /J-ketoacyl-ACP reductase (KR) / - hydroxyacyl-ACP-dehydrase (HD) enoyl-ACP reductase (ER).

Although this may seem straightforward, in some cases, the response is only indirectly related and is therefore not a useful parameter of toxicity to use in a dose-response study. This may apply to situations where enzyme inhibition is a basic parameter but where it may not relate to the overall toxic effect. For example, inhibition by lead of aminolaevulinic acid dehydrase, an enzyme, which is involved in heme synthesis, can be readily demonstrated to be dose related, but is clearly not an appropriate indicator of lead-induced renal toxicity in vivo. 

Biochemical changes such as increased aminolaevulinate excretion and inhibition of amino-laevulinate dehydrase may be detected in urine and blood, respectively, at blood lead levels of 0.4 to 0.6 mg mL-1. Anemia is a late feature, however. Neurotoxicity may be detectable at blood lead levels of 0.8 to 1.0 mg mL-1. At blood lead levels greater than 1.2 mg mL-1, encephalopathy occurs. Peripheral nerve palsies are rare, and the foot and wrist drop, which were once characteristic of occupational lead poisoning, only occur after excessive exposure and are now rarely seen. Similarly, seizures and impaired consciousness may result from involvement of the CNS. Bone changes are usually seen in children and are detected as bands at the growing ends of the bones and a change in bone shape. 

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