Disease relevance of delta-aminolevulinic acid

• We identified a point mutation resulting in an amino acid change near the pyridoxal phosphate-binding site of the erythroid 5-aminolevulinate synthase isoenzyme as the underlying defect in a kindred with X-linked pyridoxine-responsive sideroblastic anemia [1].
• Following a 3-week hospitalization, acute intermittent porphyria was diagnosed based on the symptoms and a high level of urinary delta-aminolevulinic acid (378 mumol/L [4.95 mg/dL]) [2].
• Accumulation of protoporphyrin IX from delta-aminolevulinic acid in bovine skin fibroblasts with hereditary erythropoietic protoporphyria. A gene-dosage effect [3].
• Mn- and Zn-protoporphyrin in comparable doses did not significantly inhibit ALA-induced hyperbilirubinemia [4].
• Photodynamic ablation of high-grade dysplasia and early cancer in Barrett's esophagus by means of 5-aminolevulinic acid [5].

Psychiatry related information on delta-aminolevulinic acid

• A 7-year-old boy demonstrating hepatosplenomegaly, mild anaemia, mild mental retardation, yellow-brown teeth and dark red urine had excessively elevated levels of urinary delta-aminolevulinic acid, porphobilinogen and uroporphyrin [6].

High impact information on delta-aminolevulinic acid

• The recently identified gene for an erythroid-specific 5-aminolevulinate synthase isoenzyme and its localization to the X chromosome make it likely that one or more defects in this gene underlie the anemia [1].
• We therefore sought evidence of a nucleotide-sequence abnormality in the erythroid 5-aminolevulinate synthase gene by analyzing enzymatically amplified DNA [1].
• When Chlamydomonas enzymes that convert glutamate to delta-aminolevulinic acid are separated into three fractions, one of the fractions contains RNA, and the RNA moiety is needed for the enzyme activity [7].
• The 5alphaH (A : B trans) and 5betaH (A : B cis) steroids are equipotent in inducing delta-aminolevulinic acid synthetase and porphyrin accumulation in chick embryo liver cells maintained in serum-free culture medium [8].
• Bovine skin fibroblasts accumulated protoporphyrin IX when incubated in culture with the porphyrin-heme precursor, delta-aminolevulinic acid (ALA) [3].

Chemical compound and disease context of delta-aminolevulinic acid

• Culture of Desulfovibrio vulgaris in a medium supplemented with 5-aminolevulinic acid and L-methionine-methyl-d3 resulted in the formation of porphyrins (sirohydrochlorin, coproporphyrin III, and protoporphyrin IX) in which the methyl groups at the C-2 and C-7 positions were deuterated [9].
• Pyridoxine refractory X-linked sideroblastic anemia caused by a point mutation in the erythroid 5-aminolevulinate synthase gene [10].
• Transformation of glutamate to delta-aminolevulinic acid by soluble extracts of Synechocystis sp. PCC 6803 and other oxygenic prokaryotes [11].
• In plants, algae, cyanobacteria, and many other bacteria, delta-aminolevulinic acid is synthesized from glutamate in a reaction sequence that requires three enzymes, ATP, NADPH, and tRNA(Glu) [12].
• A mutant having reduced levels of delta-aminolevulinic acid synthetase, the first unique enzyme in this pathway, was obtained in Rhizobium meliloti 102F34 by N-methyl-N'-nitro-N-nitrosoguanidine mutagenesis [13].

Biological context of delta-aminolevulinic acid

• An outer membrane protein playing a critical role in Lpp incorporation was identified, and partial amino acid sequences of the protein, named LolB, were identical to those of HemM, which has been suggested to play a role in 5-aminolevulinic acid synthesis in the cytosol [14].
• These findings accurately mirror the physiological basis for iron regulation of transferrin receptor mRNA stability as well as ferritin and erythroid 5-aminolevulinate synthase mRNA translation in vivo [15].
• No alterations in the restriction patterns of two X-linked genes involved in erythrocyte formation-i.e., a DNA-binding protein (GF-1) and 5-aminolevulinate synthase (ALAS)-were detected in DNA from affected males, arguing against a large deletion in either of these candidate genes [16].
• Hypoxic up-regulation of erythroid 5-aminolevulinate synthase [17].
• Transfection experiments showed that both Stat1alpha and Stat3 inhibited the induction by EPO of gamma-globin and erythroid-specific 5-aminolevulinate synthetase transcripts, resulting in a reduction of the percentage of hemoglobin-positive cells [18].

Anatomical context of delta-aminolevulinic acid

• In three families (designated CRIM-negative type 2), symptomatic patients had increased urinary excretion of delta-aminolevulinic acid and PBG, and normal levels of erythrocyte PBG-deaminase activity [19].
• In the presence of 25 muM iron, protoporphyrin was detected in protoporphyria cell lines when the concentration of ALA in the medium reached 50 muM, but not in normal lines [20].
• The activity of a new protease which is considered to be engaged in the regulation of delta-aminolevulinic acid synthetase levels in mitochondria of erythroblasts was shown to be in normal range in erythroblasts of the patients [21].
• We previously demonstrated an alternate pathway for the biosynthesis of 5-aminolevulinic acid (ALA) in bovine liver mitochondria and of tetrapyrroles in suspensions of rat hepatocytes (1980. J. Biol. Chem. 255: 3742; 1981. Proc. Natl. Acad. Sci. USA. 78: 5335) [22].
• Treatment of cultures with ALA and with the iron chelator, CaMgEDTA significantly increased the level of protoporphyrin IX in mitogen-stimulated lymphocytes from normal subjects, while the same treatment failed to produce an increase in protoporphyrin IX in cell preparations from EPP patients [23].

Associations of delta-aminolevulinic acid with other chemical compounds

• Administration of the synthetic metalloporphyrin, Sn-protoporphyrin, to ALA-treated neonates resulted in a dose-dependent decrease in serum bilirubin levels and hepatic heme oxygenase activity [4].
• These results indicate that disturbance of heme synthesis characteristic to pyridoxine-responsive anemia could be ascribed to the hypercatabolism of delta-aminolevulinic acid synthetase caused by the increased susceptibility to the controlling protease in erythroblasts [21].
• Normal values of porphyrin precursors, delta-aminolevulinic acid and porphobilinogen, and porphyrins were found in plasma, urine, and erythrocytes [24].
• The purpose of this study was to assess the ability of hepatocytes to synthesize porphyrins and heme from delta-aminolevulinic acid derived from gamma, delta-dioxovalerate and alanine [25].
• Bafilomycin A1 (which prevents endosome acidification) and succinylacetone (an inhibitor of 5-aminolevulinate dehydratase) prevented endosomal 59Fe incorporation into heme [26].

Gene context of delta-aminolevulinic acid

• When URO-D(+/-) mice were injected with iron-dextran and given drinking water containing delta-aminolevulinic acid for 21 days, hepatic porphyrins accumulated, and hepatic URO-D activity was reduced to 20% of wt [27].
• We show that HEM1 (encoding 5-aminolevulinate synthase) expression, while constitutive under all steady-state growth conditions tested, is activated by the HAP2-HAP3 global activation system that controls expression of apocytochromes [28].
• A promoter mutation in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causes X-linked sideroblastic anemia [29].
• Eight 5-aminolevulinic acid auxotrophic E. coli hemA mutants were genetically selected, and the corresponding mutations were determined [30].
• The mutants are unable to convert delta-aminolevulinic acid to porphobilinogen and are not complemented by the hem2 mutant GL4 (Gollub, E. G., Liu, K.-P., Dagan, J., Adlersberg, M., and Sprinson, D. B. (1977) J. Biol. Chem. 252, 2846-2854) [31].

Analytical, diagnostic and therapeutic context of delta-aminolevulinic acid

• In this assay, the ability of such cells to convert ALA to protoporphyrin was quantitated; in the sequence of reactions involved in this transformation, URO-S is limiting so that the gene defect of AIP could be simply and precisely determined by appropriate spectrofluorometry of cell extracts [32].
• Delta-aminolevulinic acid (ALA) is the precursor of porphyrin synthesis and has been recently used in vitro and in clinical studies as an endogenous photosensitizer for photodynamic therapy in the treatment of various tumors [33].
• In conclusion, oral administration of 5-aminolevulinic acid results in progressive accumulation of protoporphyrin in a transplantable colon carcinoma without accumulation in the surrounding liver tissue [34].
• The gene for erythroid 5-aminolevulinate synthase has been mapped to Xpter-Xq26 by Southern blot hybridization analysis of a mouse/human hybrid cell panel [35].
• Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis [36].

References