ALA activity

Increases in ALAS activity have been observed in lead workers (Meredith et al. 1978). Leukocyte ALAS was stimulated at a PbB level of 87 pg/dL (Meredith et al. 1978), a level at which ALAD activity is already significantly inhibited. ALAD activity correlated inversely with PbB levels in occupationally exposed individuals (Alessio et al. 1976 Wada et al. 1973), as has been seen in subjects with no occupational exposure (Secchi et al. 1974). Erythrocyte ALAD and hepatic ALAD activities were correlated directly with each other and correlated inversely with PbB levels in the range of 12-56 pg/dL (Secchi etal. 1974). 

Studies in animals indicate that the effects of lead on heme synthesis occur in many tissues and that the time courses of these effects depends on the tissue, exposure duration, and the chemical and animal species administered. Oral exposure of rats to lead acetate increased liver ALAS activity in a single dose study (Chmielnicka et al. 1994), decreased liver ALAS activity in a chronic study (Silbergeld et al. 

ALAD, and ferrochelatase. Lead indirectly stimulates the mitochondrial enzyme ALAS, which catalyzes the condensation of glycine and succinyl-coenzyme A to form ALA. The activity of ALAS is the rate-limiting step in heme biosynthesis increase of ALAS activity occurs through feedback derepression. Lead... 

Heme supply in aU tissue is controUed by the activity of mitochondrial ALAS, the first enzyme of the pathway. There are two isoforms of ALAS. The ubiquitous isoform, ALASl, is encoded by a gene on chromosome 3p21 and expressed in aU tissue. Since it has a half-life of only about an hour, changes in its rate of synthesis produce short-term alterations in enzyme concentration and cellular ALAS activity. Synthesis of ALASl is under negative feedback control by... 

The therapeutic efficacy of oral administration of seed powder of M. oleifera (500 mg/kg, orally, once daily) post arsenic exposure (100 ppm in drinking water for 4 months) in rats has been investigated (49). Animals exposed to arsenic(lll) shows a significant inhibition of 8-aminolevulinic acid dehydratase (ALAD) activity, decrease in reduced glutathione (GSH) level and an increase in reactive oxygen species (ROS) in blood. On the other hand, a significant decrease in hepatic ALAD, and an increase in 8-aminolevulinic acid synthetase (ALAS) activity is observed after arsenic exposure. These changes... 

ALAS (EC 2.3.1.37) uses PLP as a cofactor and catalyzes the one step condensation of glycine and succinyl-CoA to give rise to ALA, carbon dioxide, and free coenzyme A (Figure 3). ALAS belongs to the ct-oxoamine synthase subfamily of PLP-dependent enzymes that typically catalyze the condensation of a carboxylic acid coenzyme A thioester and an amino acid with the concomitant decarboxylation of the latter. Since the first description of ALAS activities in 1958 by Neuberger and coworkers and by Shemin and coworkers, ALAS... 

The availability of ALAS site-directed mutants of other functionally important residues permitted Tan et al. [113] to map the ALAS active site and assess whether these residues are contributed to the active site from the same subunit or from the two subunits K313, D279 and R439 are contributed to the ALAS active site from the same subrmit but different from that of R149 (Figure 2-6). 

Zebra finches Oral Pb dosing, 5-100 ppm range in diet Level of 6-ALA-D activity in erythrocytes versus PbB Log 6-ALA activity significantly negatively linked to PbB activity ratio (activated/nonactivated enzyme activity) was significantly positively linked to PbB Scheuhammer (1987)... 

Other specific discovery assays have been used such as differential inhibition of a vancomycin resistant S. aureus strain and its susceptible parent, and an assay based on antagonism of the antibacterial activity by N,A/-diacetyl-L-Lys-D-Ala-D-Ala [24570-39-6] a tripeptide analogue of the dalbaheptides receptor. AppHcation of this latter test to 1936 cultures (90) led to the isolation of 42 dalbaheptides, six of which, including kibdelin (Table 3), parvodicin (Table 3), and actinoidin A2 (68) were novel. A colorimetric assay based on competition between horseradish peroxidase bound teicoplanin and the... 

The elegant genetic studies by the group of Charles Yanofsky at Stanford University, conducted before the crystal structure was known, confirm this mechanism. The side chain of Ala 77, which is in the loop region of the helix-turn-helix motif, faces the cavity where tryptophan binds. When this side chain is replaced by the bulkier side chain of Val, the mutant repressor does not require tryptophan to be able to bind specifically to the operator DNA. The presence of a bulkier valine side chain at position 77 maintains the heads in an active conformation even in the absence of bound tryptophan. The crystal structure of this mutant repressor, in the absence of tryptophan, is basically the same as that of the wild-type repressor with tryptophan. This is an excellent example of how ligand-induced conformational changes can be mimicked by amino acid substitutions in the protein. 

Inhibitors as well as substrates bind in this crevice between the domains. From the numerous studies of different inhibitors bound to serine pro-teinases we have chosen as an illustration the binding of a small peptide inhibitor, Ac-Pro-Ala-Pro-Tyr-COOH to a bacterial chymotrypsin (Figure 11.9). The enzyme-peptide complex was formed by adding a large excess of the substrate Ac-Pro-Ala-Pro-Tyr-CO-NHz to crystals of the enzyme. The enzyme molecules within the crystals catalyze cleavage of the terminal amide group to produce the products Ac-Pro-Ala-Pro-Tyr-COOH and NHs. The ammonium ions diffuse away, but the peptide product remains bound as an inhibitor to the active site of the enzyme. 

Figure 11.9 A diagram of the active site of chymotrypsin with a bound inhibitor, Ac-Pro-Ala-Pro-Tyr-COOH. The diagram illustrates how this inhibitor binds in relation to the catalytic triad, the strbstrate specificity pocket, the oxyanion hole and the nonspecific substrate binding region. The Inhibitor is ted. Hydrogen bonds between Inhibitor and enzyme are striped. (Adapted from M.N.G. James et al., /. Mol. Biol. 144 43-88, 1980.)...

Glycine receptor function is modulated by alcohols and anesthetics [4]. Amino acid residue al(S267) is critical for alcohol potentiation, as mutation to small residues (Gly, Ala) enhance, and mutation to large residues (His, Cys, Tyr) diminish the ethanol effect. Glycine recqrtor modulation by Zn2+ involves structural determinants located within the large N-terminal domain. Additional glycinergic modulators include neuroactive steroids and the anthelmintic, ivermectin, which activates glycine receptors by a novel, strychnine-insensitive mechanism. 

Balb c mice and Wistar rats were used in the experiments. The administration of single doses of 1, 2 and 2 caused mainly necrotic changes in the liver, measured by GPT and histopathology. The extent of necrosis depended on doses and on time of observation (1-4 days after injections). In shorter time interval (2-4 hrs) 1, 2 and 2 caused depletion of hepatic GSH (even up to 10 % of control). 4 and 5 did not generate necrotic changes. Increased GPT activity was observed after 3 doses of fi. Single doses of 4, 5 and fi mostly increased the level of malondialdehyde (MDA-indicator of lipid peroxidation) in the liver. Repeated injections (3-7) of the investigated compounds enhanced the activity of ALA-D or ALA-S in the liver and caused steatosis. 

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