Disease relevance of ALAS1

• Increased heme oxygenase-1 and decreased delta-aminolevulinate synthase expression in the liver of patients with acute liver failure [1].
• Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts [2].
• Most low-GC Gram-positive bacteria came from samples with an estimated age of 5,000-8,000 years (Alas suite) [3].

High impact information on ALAS1

• This mutation resulted in decreased in vitro stability of bone marrow delta-aminolevulinate synthase activity [2].
• V-erbA acts as a constitutive repressor of erythrocyte-specific gene transcription, arresting the expression of at least three different erythroid genes: the erythrocyte anion transporter (band 3), carbonic anhydrase II (CAII) and delta-aminolevulinate synthase (ALA-S) [4].
• Upon exposure to drugs that induce cytochromes P450 and other drug-metabolizing enzymes, ALAS1 is transcriptionally up-regulated, increasing the rate of heme biosynthesis to provide heme for cytochrome P450 hemoproteins [5].
• In nonerythropoietic cells, 5-aminolevulinate synthase (ALAS1) is the rate-limiting enzyme in heme biosynthesis [5].
• Transcriptional activation of the ALAS1 gene is the first step in the coordinated up-regulation of apoprotein and heme synthesis in response to exogenous and endogenous signals controlling heme levels [5].

Biological context of ALAS1

• The ALAS1 gene was concordant with chromosome 3 in all 26 human fibroblast/murine(RAG) somatic cell hybrid clones analyzed and was discordant with all other chromosomes in at least 6 of 26 clones [6].
• In contrast to HO-1, ALAS1 gene expression was markedly down-regulated in ALF patients compared with controls [1].
• Human delta-aminolevulinate synthase: assignment of the housekeeping gene to 3p21 and the erythroid-specific gene to the X chromosome [6].
• Alternative splicing of human ALAS1 generates two mRNAs with different 5'-UTRs: a major one, where exon 1B is omitted, and a minor form containing exon 1B [7].
• Haem controls its own synthesis in non-erythroid cells primarily by regulation of ALAS1 mRNA stability [7].

Anatomical context of ALAS1

• Using these different cDNAs, the human ALAS housekeeping gene (ALAS1) and the human erythroid-specific (ALAS2) gene have been localized to chromosomes 3p21 and X, respectively, by somatic cell hybrid and in situ hybridization techniques [6].
• Differentiation of embryonic stem cells with a disrupted ALAS2 gene has established that expression of this gene is critical for erythropoiesis and cannot be compensated by expression of the ubiquitous isoform of the enzyme (ALAS1) [8].
• While heme negatively regulates the synthesis of the housekeeping delta-aminolevulinate synthase (ALAS-N) in all non-erythroid cells, the expression of an erythroid-specific isozyme (ALAS-E) is developmentally regulated in red blood cells [9].
• Two of the major organs producing heme are bone marrow and the liver. delta-Aminolevulinate synthase (ALAS) plays the key role to regulate heme biosynthesis in hepatocytes as well as in erythroid cells [10].
• The first enzyme, ALAS (5-aminolaevulinate synthase), occurs as an isoenzyme encoded on different chromosomes and is synthesized either as a housekeeping protein (ALAS-1) in all non-erythroid cell types, or only in differentiating erythroid precursor cells (ALAS-2) [11].

Associations of ALAS1 with chemical compounds

• It has been shown that a deficiency of the erythroid-specific delta-aminolevulinate synthase (ALAS-E) activity is responsible for pyridoxine-responsive HSA in many patients, however, the pathogenesis of other types of HSA remains still unknown [12].
• Induction of delta-aminolevulinate synthase and cytochrome P-450 hemoproteins in hepatocyte culture. Effect of glucose and hormones [13].
• Increased glutathione in cultured hepatocytes associated with induction of cytochrome P-450. Lack of effect of glutathione depletion on induction of cytochrome P-450 and delta-aminolevulinate synthase [14].
• In primary cultures of chick embryo hepatocytes pulse labeled with [35S]methionine, immunochemical analyses indicated that adenosine 3':5'-cyclic monophosphate (cAMP) did not affect either the rate of production or the maturation of delta-aminolevulinate synthase (ALA synthase) [15].
• Glutathione depletion did not affect the ability of 2-propyl-2-isopropylacetamide to induce cytochrome P-450, glucuronidation of phenol red, or delta-aminolevulinate synthase [14].

Other interactions of ALAS1

• These findings suggest that, in the liver of ALF patients, there may be an increase in free heme concentration which up-regulates HO-1 gene expression, while down-regulating ALAS1 gene expression, resulting in markedly altered heme metabolism and liver function [1].
• 1. PCR analysis of somatic cell and radiation hybrids localized ALAS1 to the same distal region of 3p21.1 as the aminoacylase-1 gene [16].
• HPRT1, ALAS1, and K-ALPHA-1 were calculated by both programs to be the most stable genes covering a broad range of expression [17].
• Our results suggest that the fundamental mechanism of drug induction is the same for cytochromes P450 and ALAS1 [5].
• Incubating cells with 5-aminolevulinic acid (thus bypassing the rate-limiting step in heme biosynthesis, 5-aminolevulinic acid synthase) led to a decrease in transferrin receptor number [18].

Analytical, diagnostic and therapeutic context of ALAS1

• The regional localization of ALAS1 to 3p21 was accomplished by in situ hybridization using the 125I-labeled human ALAS1 cDNA [6].
• Assignment of the human housekeeping delta-aminolevulinate synthase gene (ALAS1) to chromosome band 3p21.1 by PCR analysis of somatic cell hybrids [16].

References