5- Aminolevulinate synthetase

Hepatocytes were treated as described in Table III, and activities of 8-aminolevulinate synthetase (ALAS), ferrochelatase, and heme oxygenase were determined as described previously (Kim et aL, 1995). NMMA, N -monomethyl-L-arginine SNAP, S-nitrosoacetylpenacillamine. 

Hockin, L.J. and Paine, A.J. (1983). The role of 5-aminolevulinate synthetase, haem oxygenase and ligand formation in the mechanism of maintenance of cytochrome P-450 concentration in hepatocyte culture. Biochem. Pharmacol. 210 855-857. 

Scheme XIII. Stereochemical alternatives in the 5-aminolevulinate synthetase reaction (end-on view down the C-a-N bond the dashed line represents the plane of the tr system of the Schiffs base and pyridine ring).

Aminolevulinate synthetase catalyzes the condensation of the Schiff s base of glycine with succinoyl-CoA. Recently, it has been found that 2-amino-4-methoxv-trans-3-butenolc acid, previously found to inhibit aspartate aminotransferase (13). also irreversibly Inactivates this enzyme (34). 

C) 5-aminolevulinate synthetase catalyzes the regulated and rate-limiting step in heme biosynthesis... 

Pyridoxal-P-dependent 5-aminolevulinate synthetase catalyses the formation of 5-aminolevulinic acid from glycine and succinyl-CoA, and this constitutes the first irreversible step on the main pathway leading to the biosynthesis of tetrapyrroles. ALA synthetase [61] has been purified from several bacterial, avian and mammalian sources, but the amount of enzyme obtained in these preparations is relatively small. Light-grown Rhodopseudomonas spheroides is at present the best source of the... 

In Pennisetum seedlings treated with difunon in higher concentration (>10 iM), the bleaching of pigments was reported to be paralleled by a decrease of the porphobilinogenase level whereas the contents of -aminolevulinic synthetase and dehydratase were not lowered ( 4). This proposed mode of action of difvinon upon chlorophyll biosynthesis could not be confirmed with the microalga Chlorella (23). 

Neuberger et al. have shown that thiocystine (and other related trisulfides) can convert aminolevulinate synthetase of spheroides from a low activity to a high activity form. Wood and co-workers found thiocystine, when injected intravenously into rats just prior to i.p. cyanide, will protect the animals against 3 times the LD50. Also, the compound provides some protection against radiation. Thiocystine can replace cystine in the diet of growing rats. 

Fig. 6. Derepression without growth. Cells growing exponentially on 5% glucose were treated as described in the text and placed in derepression medium at a density of 1.1 x 10 ml There was no (< 10%) increase in whole cell protein in the course of the experiment, while dry-weight and cell number each increased by 30%. (A) Increase in specific activity of standard battery of enzymes (for abbreviations see Table IV). (B) Derepression pattern exhibited by 6-aminolevulinate synthetase, assayed as described by Marwer et al Two separate experiments (filled and empty symbols) are shown.

Narayan S, Misra UK. 1985. Delta-aminolevulinic acid synthetase and heme oxygenase activity in lung and liver of rats given DDT and endosulfan intratracheally. Bull Environ Contam Toxicol 34 24-28. 

Various minor hematological effects have been noted in animals. Rats exposed to 50-800 ppm of trichloroethylene continuously for 48 or 240 hours showed time- and dose-related depression of delta-aminolevulinate dehydratase activity in liver, bone marrow, and erythrocytes (Fujita et al. 1984 Koizumi et al. 1984). Related effects included increased delta-aminolevulinic acid (ALA) synthetase activity, reduced heme saturation of tryptophan pyrrolase and reduced cytochrome P-450 levels in the liver and increased urinary excretion of... 

Decrease in weight gain moderate liver pathology gross accumulations of hepatic porphyrins and increased delta-aminolevulinic acid synthetase activity Decrease in weight gain comparatively small increase in liver weight... 

Pretreatment with the Type I substrate, ethylmorphine, resulted in 100% mortality in both rats and mice, and aminopyrine pretreatment resulted in 100% and 64% mortality in rats and mice, respectively, exposed to disulfoton (Pawar and Fawade 1978). Nickel chloride, cobalt chloride, or cycloheximide decreased the levels of cytochrome bs, cytochrome c reductase, and total heme in rats (Fawade and Pawar 1983). These electron transport components were further decreased in rats pretreated with these inhibitors and given a single dose of disulfoton. Data from this study suggests an additive effect, since disulfoton also decreases the activities of these components. Evidence of an additive effect between disulfoton and these metabolic inhibitors was suggested by the decrease in ethylmorphine N-demethylase and acetanilide hydroxylase activities when rats were given an inhibitor followed by disulfoton. In another experiment, these inhibitors decreased the activity of delta-aminolevulinic acid synthetase, but this decrease was reversed when disulfoton was administered. 

Although generalizations regarding the hematological effects of fuel oils on humans cannot be made, the effect of kerosene on the first two steps of the heme synthetic pathway has been studied in an animal model. Both hepatic -aminolevulinic acid ( -ALA) dehydratase and -ALA synthetase activities were decreased in female rats after intraperitoneal injection of kerosene, while heme oxygenase was unaffected (Rao and Pandya 1980). Since -ALA synthetase is the rate-limiting enzyme of the heme biosynthesis pathway, hepatic heme biosynthesis may be inhibited by kerosene. It is conceivable that this may be related to the extramedullary hematopoiesis reported in other studies (NTP/NIH 1986) however, there are no direct data to support this. 

Although not specific for kerosene, aminolevulinic acid (ALA) could potentially be used as an adjunct or supplemental biomarker for kerosene exposure. Kerosene may affect heme metabolism by decreasing the activities of enzymes in the heme biosynthetic pathway (hepatic -ALA dehydratase and -ALA synthetase) (Rao and Pandya 1980). Therefore, it may be possible that this effect would generate increased ALA in the urine of exposed individuals. Additional studies of acute, intermediate, and chronic exposure are needed to identify biomarkers of effects for specific target organs following exposure to fuel oils. 

ALANYL-CoA AMMONIA LYASE 5-AMINOLEVULINATE SYNTHASE ARACHIDONYL-CoA SYNTHETASE... 

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