6-Aminolevulinate

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),... 

Lead-induced anemia results from impairment of heme biosynthesis and acceleration of red blood cell destmction (10,13). Lead-induced inhibition of heme biosynthesis is caused by inhibition of S-aminolevulinic acid dehydratase and ferrochelatase which starts to occur at blood lead levels of 10 to 20 pu gjdL and 25 to 30 //g/dL, respectively (10,13). Anemia, however, is not manifested until higher levels are reached. 

Aminolevulinic acid dehydratase 3-aminotriazole toxicity to, 1, 139 Aminopterin—see Folic acid, 4-amino-Aminopyrine as antipyretic, 1, 172 biological activity, 5, 295 Aminyl, dimethyl-ESR, 7, 19 Amiphenazole... 

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

ALAD (8-aminolevulinic acid dehydratase) Aldehydes (screening)... 

Chlorophyll, heme, vitamin B,2, and a host of other substances are bio-synthesized from porphobilinogen (PEG), which is itself formed from condensation of two molecules of 5-aminolevulinate. The two 5-aminolevulinates are bound to lysine (Lys) amino acids in the enzyme, one in the enamine form and one in the imine form, and their condensation is thought to occur by the following steps. Using curved arrows, show the mechanism of each step. 

Pyridoxamine phosphate serves as a coenzyme of transaminases, e.g., lysyl oxidase (collagen biosynthesis), serine hydroxymethyl transferase (Cl-metabolism), S-aminolevulinate synthase (porphyrin biosynthesis), glycogen phosphoiylase (mobilization of glycogen), aspartate aminotransferase (transamination), alanine aminotransferase (transamination), kynureninase (biosynthesis of niacin), glutamate decarboxylase (biosynthesis of GABA), tyrosine decarboxylase (biosynthesis of tyramine), serine dehydratase ((3-elimination), cystathionine 3-synthase (metabolism of methionine), and cystathionine y-lyase (y-elimination). 

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. 

Gold MH, Goldman MP (2004) 5-aminolevulinic acid photodynamic therapy where we have been and where we are going. Dermatol Surg 30 1077-1083... 

Pariser DM, Lowe NJ, Stewart DM, Jarratt MT, Lucky AW, Pariser RJ, Yamauchi PS (2003) Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis results of a prospective randomized multicenter trial. J Am Acad Dermatol 48 227-232... 

X-linked sideroblastic anemia is not a porphyria but is included here because 6-aminolevulinic acid synthase is involved. 

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... 

Fujita H, Koizumi A, Yamamoto M, et al. 1984. Inhibition of delta-aminolevulinate dehydratase in trichloroethylene-exposed rats, and the effects on heme regulation. Biochem Biophys Acta 800 1-10. 

The biosynthesis of the tetrapyrrole macrocycle and its branches leading to haem and chlorophylls has been covered in detail in several reviews - - and will be concisely described in this section. Tetrapyrrole biosynthesis occurs entirely in the plastids and is composed of several enzymatic steps starting from 5-aminolevulinic acid (ALA), which is the key precursor of porphyrins and the source of their carbon and nitrogen. 

FIGURE 2.1.3 Synthesis of 5-aminolevulinic acid (ALA) by the C-5 pathway (from a-ketoglutarate or glutamate) and the C-4 pathway (condensation of succinyl CoA with glycine). 

Beale, S.I. and Castelfranco, P.A., The biosynthesis of 5-aminolevulinic acid in plants. II. Formation of C-5-Aminolevulinic acid from labeled precursors in greening plant tissues, Plant Physiol, 53, 297, 1974. 

Beale, S.I., 5-Aminolevulinic acid in plants its biosynthesis, regulation and role in plastid development, Annu. Rev. Plant Physiol, 29, 95, 1978. 

The most common method used to monitor inorganic Pb is the determination of Pb in whole blood by GF-AAS. Exposure to organic lead (i.e. tetraethyl lead) can be monitored by the determination of Pb in mine by GF-AAS (Christensen and Kristiansen 1994). Early effects of exposure to Pb on the heme synthesis can be monitored by determination of the inhibition of the enayme 8-aminolevulinic acid dehydratase in whole blood or 8-aminolevulinic acid in urine by spectrophotometry. 

Alterations in blood heme metabolism have been proposed as a possible indicator of the biological effects of hydrogen sulfide (Jappinen and Tenhunen 1990), but this does not relate to the mechanism of toxicity in humans. The activities of the enzymes of heme synthesis, i.e., delta-aminolevulinic acid synthase (ALA-S) and heme synthase (Haem-S), were examined in 21 cases of acute hydrogen sulfide toxicity in Finnish pulp mill and oil refinery workers. Subjects were exposed to hydrogen sulfide for periods ranging from approximately 1 minute to up to 3.5 hours. Hydrogen sulfide concentrations were considered to be in the range of 20-200 ppm. Several subjects lost consciousness for up to 3 minutes. 

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