Disease relevance of ALAS1

• ALAS1 drug-responsive enhancer sequences were identified by transient transfection of reporter gene constructs in the drug-responsive leghorn male hepatoma cell line [1].
• Parameters used to assess toxicity were: (1) release of lactate dehydrogenase (LDH); (2) decreased induction of 5-aminolevulinic acid synthase (ALAS), measured as porphyrin accumulation; and (3) decreased protein synthesis [2].

High impact information on ALAS1

• Differential effects of metalloporphyrins on messenger RNA levels of delta-aminolevulinate synthase and heme oxygenase. Studies in cultured chick embryo liver cells [3].
• A controversy has existed in the literature for the past several years regarding the number of vertebrate genes encoding the mitochondrial protein that initiates the first step in heme biosynthesis, delta-aminolevulinate synthase [ALAS; succinyl-CoA: glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37] [4].
• We performed experiments in primary chick embryo liver cells with tin-, zinc- and copper-chelated porphyrins to assess their effects on activities of delta-aminolevulinate synthase induced by prior treatment of cells with glutethimide and ferric nitrilotriacetate [5].
• Inhibitors of P-450-phenobarbital, SKF525A and piperonyl butoxide, as well as cadmium and cycloheximide prevented the porphyrin accumulation produced by glutethimide + iron, even though, except with cycloheximide, these substances further increased 5-aminolevulinate synthase activity [6].
• Transactivation assays in CV-1 cells implicate the nuclear receptors as major contributors to transcriptional activation of ALAS1 [1].

Chemical compound and disease context of ALAS1

• We investigated the effects on the avian ALAS-1 gene promoter of a phenobarbital-like chemical, Glut (glutethimide), and a haem synthesis inhibitor, DHA (4,6-dioxoheptanoic acid), using a reporter gene assay in transiently transfected LMH (Leghorn male hepatoma) hepatoma cells [7].

Biological context of ALAS1

• Nucleotide sequence of the chicken 5-aminolevulinate synthase gene [8].
• We have identified a drug-responsive enhancer in the murine ALAS1 gene [1].
• Using the NUBIScan algorithm, DR4 nuclear receptor binding sites were identified within the elements and their roles in mediating transcriptional activation of ALAS1 were confirmed by site-directed mutagenesis [1].
• These studies are the first to explain drug induction via drug response elements for mammalian ALAS1 [1].
• In the present studies, a chicken genomic cosmid library was employed to isolate a major portion of the ALAS1 gene [9].

Anatomical context of ALAS1

• It is concluded that subunit of embryonic chick liver delta-aminolevulinate synthase present in mitochondria has a molecular weight of 65,000 and appears to be synthesized as a precursor of 75,000 daltons [10].
• We also show that a single mRNA species for 5-aminolevulinate synthase is present in chicken liver, reticulocytes, brain, and heart and an avian erythroblastosis virus-transformed chicken erythroblast cell line [11].
• The essential features of hepatic protoporphyria, namely inhibition of ferrochelatase, accumulation of protoporphyrin and stimulation of 5-aminolevulinic acid synthase (ALA-S) were all obtained by treating chicken hepatocytes in culture with small doses of N-methylprotoporphyrin [12].
• We have examined the effect of heme on the activity of native delta-aminolevulinate synthase isolated from drug-induced chick embryo liver mitochondria [13].
• delta-Aminolevulinate synthase isozymes in the liver and erythroid cells of chicken [14].

Associations of ALAS1 with chemical compounds

• In contrast, chromium(VI) treatment had significant but opposite effects on the basal and drug-inducible expression of 5-aminolevulinate synthase and cytochrome PB1 P450 [15].
• The influence of propranolol on the concentration of heme and on the activity of delta aminolevulinate synthase in monolayers of chick embryo liver cells [16].
• The substituted pyridines metyrapone and nicotinamide are inducers of 5-aminolevulinate synthase and cytochrome P-450 in hepatocyte culture [17].
• The present study examines the effect of inhibiting protein synthesis with cycloheximide on the induction of the genes for cytochrome P4502H1 (CYP2H1) and 5-aminolevulinate synthase (ALAS) in phenobarbital-treated chick embryo livers [18].
• Arsenite had no effect on induction of 5-aminolevulinic acid synthase mRNA or activity [19].

Other interactions of ALAS1

• In the present study, we report that the protein kinase inhibitor 2-aminopurine markedly inhibits the phenobarbital-induced activation of CYP2H1 and ALAS-1 genes as measured by Northern blot analysis, but does not alter the basal expression of these genes in the absence of drug [20].

Analytical, diagnostic and therapeutic context of ALAS1

• Electrophoretic mobility shift assays and transactivation studies demonstrate direct interactions between the nuclear receptor binding sites and the recently described chicken xenobiotic-sensing receptor, (CXR) implicating drug activation mechanisms for ALAS1 similar to those found in inducible cytochrome(s) P450 [9].
• From Northern blot analysis the size of the mRNA for 5-aminolevulinate synthase was estimated to be 2800 base pairs, approximately 600 base pairs more than that required to code for the primary translation product of relative molecular mass 74000 [21].
• Molecular cloning of hepatic 5-aminolevulinate synthase [21].

References